Amine derivative compounds for treating ophthalmic diseases and disorders

ABSTRACT

Provided are amine derivative compounds, pharmaceutical compositions thereof, and methods of treating ophthalmic diseases and disorders, such as age-related macular degeneration and Stargardt&#39;s Disease, using said compounds and compositions.

CROSS-REFERENCE

This application is a divisional application of U.S. patent applicationSer. No. 14/226,665 filed Mar. 26, 2014, which is a divisional of U.S.application Ser. No. 13/278,925, filed Oct. 21, 2011, now U.S. Pat. No.8,716,529, issued on May 6, 2014, which is a continuation of U.S.application Ser. No. 12/256,415, filed Oct. 22, 2008, now U.S. Pat. No.8,076,516, issued on Dec. 13, 2011, which claims the benefit of U.S.Provisional Application No. 60/984,667, filed Nov. 1, 2007, all of whichare incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Neurodegenerative diseases, such as glaucoma, macular degeneration, andAlzheimer's disease, affect millions of patients throughout the world.Because the loss of quality of life associated with these diseases isconsiderable, drug research and development in this area is of greatimportance.

Age-related macular degeneration (AMD) affects between ten and fifteenmillion patients in the United States, and it is the leading cause ofblindness in aging populations worldwide. AMD affects central vision andcauses the loss of photoreceptor cells in the central part of retinacalled the macula. Macular degeneration can be classified into twotypes: dry-form and wet-form. The dry-form is more common than the wet;about 90% of age-related macular degeneration patients are diagnosedwith the dry-form. The wet-form of the disease and geographic atrophy,which is the end-stage phenotype of dry-form AMD, causes the mostserious vision loss. All patients who develop wet-form AMD are believedto previously have developed dry-form AMD for a prolonged period oftime. The exact causes of AMD are still unknown. The dry-form of AMD mayresult from the senescence and thinning of macular tissues associatedwith the deposition of pigment in the macular retinal pigmentepithelium. In wet-form AMD, new blood vessels grow beneath the retina,form scar tissue, bleed, and leak fluid. The overlying retina can beseverely damaged, creating “blind” areas in the central vision.

For the vast majority of patients who have the dry-form of AMD, noeffective treatment is yet available. Because the dry-form of AMDprecedes development of the wet-form of AMD, therapeutic intervention toprevent or delay disease progression in the dry-form of AMD wouldbenefit patients with dry-form AMD and might reduce the incidence of thewet-form of AMD.

Decline of vision noticed by the patient or characteristic featuresdetected by an ophthalmologist during a routine eye exam may be thefirst indicator of AMD. The formation of “drusen,” or membranous debrisbeneath the retinal pigment epithelium of the macula is often the firstphysical sign that AMD is developing. Late symptoms include theperceived distortion of straight lines and, in advanced cases, a dark,blurry area or area with absent vision appears in the center of vision;and/or there may be color perception changes.

Different forms of genetically-linked macular degenerations may alsooccur in younger patients. In other maculopathies, factors in thedisease are heredity, nutritional, traumatic, infection, or otherecologic factors.

Glaucoma is a broad term used to describe a group of diseases thatcauses a slowly progressive visual field loss, usually asymptomatically.The lack of symptoms may lead to a delayed diagnosis of glaucoma untilthe terminal stages of the disease. The prevalence of glaucoma isestimated to be 2.2 million in the United States, with about 120,000cases of blindness attributable to the condition. The disease isparticularly prevalent in Japan, which has four million reported cases.In many parts of the world, treatment is less accessible than in theUnited States and Japan, thus glaucoma ranks as a leading cause ofblindness worldwide. Even if subjects afflicted with glaucoma do notbecome blind, their vision is often severely impaired.

The progressive loss of peripheral visual field in glaucoma is caused bythe death of ganglion cells in the retina. Ganglion cells are a specifictype of projection neuron that connects the eye to the brain. Glaucomais usually accompanied by an increase in intraocular pressure. Currenttreatment includes use of drugs that lower the intraocular pressure;however, contemporary methods to lower the intraocular pressure areoften insufficient to completely stop disease progression. Ganglioncells are believed to be susceptible to pressure and may sufferpermanent degeneration prior to the lowering of intraocular pressure. Anincreasing number of cases of normal-tension glaucoma are observed inwhich ganglion cells degenerate without an observed increase in theintraocular pressure. Current glaucoma drugs only treat intraocularpressure and are ineffective in preventing or reversing the degenerationof ganglion cells.

Recent reports suggest that glaucoma is a neurodegenerative disease,similar to Alzheimer's disease and Parkinson's disease in the brain,except that it specifically affects retinal neurons. The retinal neuronsof the eye originate from diencephalon neurons of the brain. Thoughretinal neurons are often mistakenly thought not to be part of thebrain, retinal cells are key components of the central nervous system,interpreting the signals from the light-sensing cells.

Alzheimer's disease (AD) is the most common form of dementia among theelderly. Dementia is a brain disorder that seriously affects a person'sability to carry out daily activities. Alzheimer's is a disease thataffects four million people in the United States alone. It ischaracterized by a loss of nerve cells in areas of the brain that arevital to memory and other mental functions. Currently available drugscan ameliorate AD symptoms for a relatively finite period of time, butno drugs are available that treat the disease or completely stop theprogressive decline in mental function. Recent research suggests thatglial cells that support the neurons or nerve cells may have defects inAD sufferers, but the cause of AD remains unknown. Individuals with ADseem to have a higher incidence of glaucoma and age-related maculardegeneration, indicating that similar pathogenesis may underlie theseneurodegenerative diseases of the eye and brain. (See Giasson et al.,Free Radic. Biol. Med. 32:1264-75 (2002); Johnson et al., Proc. Natl.Acad. Sci. USA 99:11830-35 (2002); Dentchev et al., Mol. Vis. 9:184-90(2003).

Neuronal cell death underlies the pathology of these diseases.Unfortunately, very few compositions and methods that enhance retinalneuronal cell survival, particularly photoreceptor cell survival, havebeen discovered. A need therefore exists to identify and developcompositions that can be used for treatment and prophylaxis of a numberof retinal diseases and disorders that have neuronal cell death as aprimary, or associated, element in their pathogenesis.

In vertebrate photoreceptor cells, the irradiance of a photon causesisomerization of 11-cis-retinylidene chromophore toall-trans-retinylidene and uncoupling from the visual opsin receptors.This photoisomerization triggers conformational changes of opsins,which, in turn, initiate the biochemical chain of reactions termedphototransduction (Filipek et al., Annu. Rev. Physiol. 65:851-79(2003)). Regeneration of the visual pigments requires that thechromophore be converted back to the 11-cis-configuration in theprocesses collectively called the retinoid (visual) cycle (see, e.g.,McBee et al., Prog. Retin. Eye Res. 20:469-52 (2001)). First, thechromophore is released from the opsin and reduced in the photoreceptorby retinol dehydrogenases. The product, all-trans-retinol, is trapped inthe adjacent retinal pigment epithelium (RPE) in the form of insolublefatty acid esters in subcellular structures known as retinosomes(Imanishi et al., J. Cell Biol. 164:373-87 (2004)).

In Stargardt's disease (Allikmets et al., Nat. Genet. 15:236-46 (1997)),a disease associated with mutations in the ABCR transporter that acts asa flippase, the accumulation of all-trans-retinal may be responsible forthe formation of a lipofuscin pigment, A2E, which is toxic towardsretinal pigment epithelial cells and causes progressive retinaldegeneration and, consequently, loss of vision (Mata et al., Proc. Natl.Acad. Sci. USA 97:7154-59 (2000); Weng et al., Cell 98:13-23 (1999)).Treating patients with an inhibitor of retinol dehydrogenases, 13-cis-RA(Isotretinoin, Accutane®, Roche), has been considered as a therapy thatmight prevent or slow the formation of A2E and might have protectiveproperties to maintain normal vision (Radu et al., Proc. Natl. Acad.Sci. USA 100:4742-47 (2003)). 13-cis-RA has been used to slow thesynthesis of 11-cis-retinal by inhibiting 11-cis-RDH (Law et al.,Biochem. Biophys. Res. Commun. 161:825-9 (1989)), but its use can alsobe associated with significant night blindness. Others have proposedthat 13-cis-RA works to prevent chromophore regeneration by bindingRPE65, a protein essential for the isomerization process in the eye(Gollapalli et al., Proc. Natl. Acad. Sci. USA 101:10030-35 (2004)).Gollapalli et al. reported that 13-cis-RA blocked the formation of A2Eand suggested that this treatment may inhibit lipofuscin accumulationand, thus, delay either the onset of visual loss in Stargardt's diseaseor age-related macular degeneration, which are both associated withretinal pigment-associated lipofuscin accumulation. However, blockingthe retinoid cycle and forming unliganded opsin may result in moresevere consequences and worsening of the patient's prognosis (see, e.g.,Van Hooser et al., J. Biol. Chem. 277:19173-82 (2002); Woodruff et al.,Nat. Genet. 35:158-164 (2003)). Failure of the chromophore to form maylead to progressive retinal degeneration and may produce a phenotypesimilar to Leber Congenital Amaurosis (LCA), which is a very raregenetic condition affecting children shortly after birth.

SUMMARY OF THE INVENTION

A need exists in the art for an effective treatment for treatingophthalmic diseases or disorders resulting in ophthalmic dysfunctionincluding those described above. In particular, there exist is apressing need for compositions and methods for treating Stargardt'sdisease and age-related macular degeneration (AMD) without causingfurther unwanted side effects such as progressive retinal degeneration,LCA-like conditions, night blindness, or systemic vitamin A deficiency.A need also exists in the art for effective treatments for otherophthalmic diseases and disorders that adversely affect the retina.

The present invention relates to amine derivative compounds, which areinhibitors of an isomerization step of the retinoid cycle and are usefulfor treating ophthalmic diseases and disorders. Also provided arepharmaceutical compositions comprising the amine derivative compoundsand methods for treating various ophthalmic diseases, using thesecompounds.

Accordingly, in one embodiment, is a compound of Formula (A) ortautomer, stereoisomer, geometric isomer or a pharmaceuticallyacceptable solvate, hydrate, salt, N-oxide or prodrug thereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷) or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or    -   R³⁶ and R³⁷ together form an oxo; or optionally, R³⁶ and R¹        together form a direct bond to provide a double bond; or        optionally, R³⁶ and R¹ together form a direct bond, and R³⁷ and        R² together form a direct bond to provide a triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;    -   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,        carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or        SO₂NR²⁴R²⁵; or R⁷ and R⁸ together with the nitrogen atom to        which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰ carbocyclyl; or R⁹ and R¹⁰ form an    oxo; or optionally, R⁹ and R¹ together form a direct bond to provide    a double bond; or optionally, R⁹ and R¹ together form a direct bond,    and R¹⁰ and R² together form a direct bond to provide a triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; with the provision that G is    not an unsubstituted normal alkyl and the provision that the    compound of Formula A is not:

In another embodiment is the compound of Formula (A) wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;    -   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,        carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or        SO₂NR²⁴R²⁵; or R⁷ and R⁸ together with the nitrogen atom to        which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or R¹¹ and    R¹², together with the nitrogen atom to which they are attached,    form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In another embodiment is the compound of Formula (A) having thestructure of Formula (B)

-   wherein,-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)— or —O—C(R³¹)(R³²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo; or optionally, R⁹ and R¹ together form a    direct bond to provide a double bond; or optionally, R⁹ and R¹    together form a direct bond, and R¹⁰ and R² together form a direct    bond to provide a triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹, and R³⁴ are each independently hydrogen or alkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl.

In another embodiment is the compound of Formula (B) wherein,

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)— or —O—C(R³¹)(R³²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹, and R³⁴ are each independently hydrogen or alkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo.

In another embodiment is the compound of Formula (B) having thestructure of Formula (C)

wherein,

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)— or —O—C(R³¹)(R³²)—;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo; or optionally, R⁹ and R¹ together form a    direct bond to provide a double bond; or optionally, R⁹ and R¹    together form a direct bond, and R¹⁰ and R² together form a direct    bond to provide a triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹, and R³⁴ are each independently hydrogen or alkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl.

In another embodiment is the compound of Formula (C) wherein,

-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo.

In another embodiment is the compound of Formula (C) having thestructure of Formula (D):

wherein,

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹ and R³⁴ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    to which they are attached form a carbocyclyl or heterocycle;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; and-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl.

In another embodiment is the compound of Formula (D) wherein n is 0 andeach of R¹¹ and R¹² is hydrogen. in a further embodiment is the compoundwherein each of R³, R⁴, R¹⁴ and R¹⁵ is hydrogen. In a further embodimentis the compound wherein,

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle; and-   R¹⁸ is selected from a hydrogen, alkoxy or hydroxy.

In a further embodiment is the compound wherein R¹⁶ and R¹⁷, togetherwith the carbon to which they are attached, form a cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and R¹⁸is hydrogen or hydroxy.

In another embodiment is the compound of Formula (D), wherein R¹¹ ishydrogen and R¹² is —C(═O)R²³, wherein R²³ is alkyl.

In a further embodiment is the compound of Formula (D), wherein

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy or alkoxy.

In a further embodiment is the compound of Formula (D) wherein,

-   n is 0;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a cyclopentyl, cyclohexyl or cyclohexyl; and-   R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (D) wherein,

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷ is independently selected from C₁-C₁₃ alkyl; and R¹⁸ is    hydrogen, hydroxy or alkoxy.

In another embodiment is the compound of Formula (C) having thestructure of Formula (E):

wherein,

-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, or —C(═O)R²³; or R¹¹ and R¹², together with the    nitrogen atom to which they are attached, form an N-heterocyclyl;-   R²³ is selected from alkyl, alkenyl, aryl, carbocyclyl, heteroaryl    or heterocyclyl;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    atom to which they are attached, form a carbocyclyl or heterocycle;-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   R³⁴ is hydrogen or alkyl; and-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In another embodiment is the compound of Formula (E) wherein n is 0 andeach of R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (E) wherein each R³,R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (E) wherein,

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy, or alkoxy.

In a further embodiment is the compound of Formula (E) wherein R¹⁶ andR¹⁷, together with the carbon atom to which they are attached form acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (E) wherein, R³¹ andR³² are each independently selected from hydrogen, or C₁-C₅ alkyl; andR¹⁸ is hydrogen, hydroxy or alkoxy.

In a further embodiment is the compound of Formula (E) wherein,

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷ is independently selected from C₁-C₁₃ alkyl; and-   R¹⁸ is hydrogen, hydroxy or alkoxy.

In another embodiment is the compound of Formula (A) wherein,

-   Z is a bond, —X—C(R³¹)(R³²)—, or —X—C(R³¹)(R³²)—C(R¹)(R²)—; and-   X is —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—.

In a further embodiment is the compound of Formula (A) wherein,

-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo.

In another embodiment is the compound of Formula (A) having thestructure of Formula (F):

wherein,

-   X is —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, or —C(═O)R²³; or R¹¹ and R¹², together with the    nitrogen atom to which they are attached, form an N-heterocyclyl;-   R²³ is selected from alkyl, alkenyl, aryl, carbocyclyl, heteroaryl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    atom to which they are attached, form a carbocyclyl or heterocycle;-   R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the compound of Formula (F) wherein n is 0and each R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (F) wherein each R³,R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (F) wherein,

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl or heterocycle; and-   R¹⁸ is hydrogen, hydroxy, or alkoxy.

In a further embodiment is the compound of Formula (F) wherein R¹⁶ andR¹⁷, together with the carbon atom to which they are attached form acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (F) wherein, R³¹ andR³² are each independently selected from hydrogen, or C₁-C₅ alkyl; R¹⁶and R¹⁷ is independently selected from C₁-C₁₃ alkyl; and R¹⁸ ishydrogen, hydroxy or alkoxy.

In one embodiment is a compound having a structure of Formula (I):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:

R¹ and R² are each the same or different and independently hydrogen,halogen, C₁-C₅ alkyl, fluoroalkyl, —OR⁶, or —NR⁷R; or R¹ and R² form anoxo;

-   R³ and R⁴ are each the same or different and independently hydrogen    or alkyl;-   R⁵ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or    carbocyclylalkyl;-   R⁶ is hydrogen or alkyl;-   R⁷ and R⁸ are each the same or different and independently hydrogen,    alkyl, carbocyclyl, or —C(═O)R¹³; or-   R⁷ and R⁸, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —C(R⁹)(R¹⁰)— or —O—;-   R⁹ and R¹⁰ are each the same or different and independently    hydrogen, halogen, alkyl, fluoroalkyl, —OR⁶, —NR⁷R⁸ or carbocyclyl;    or R⁹ and R¹⁰ form an oxo;-   R¹¹ and R¹² are each the same or different and independently    hydrogen, alkyl, or —C(═O)R¹³; or-   R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   R¹³ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or    heterocyclyl.

In another embodiment is the compound of Formula (I) having a structureof Formula (Ia):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:

-   R¹ and R² are each the same or different and independently hydrogen,    halogen, C₁-C₅ alkyl, fluoroalkyl, —OR⁶, or —NR⁷R; or R¹ and R² form    an oxo;-   R³ and R⁴ are each the same or different and independently hydrogen    or alkyl;-   R⁵ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or    carbocyclylalkyl;-   R⁶ is hydrogen or alkyl;-   R⁷ and R⁸ are each the same or different and independently hydrogen,    alkyl, carbocyclyl, or —C(═O)R¹³; or-   R⁷ and R⁸, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each the same or different and independently    hydrogen, halogen, alkyl, fluoroalkyl, —OR⁶, —NR⁷R⁸ or carbocyclyl;    or R⁹ and R¹⁰ form an oxo;-   R¹¹ and R¹² are each the same or different and independently    hydrogen, alkyl, or —C(═O)R¹³; or-   R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   R¹³ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or    heterocyclyl.

In a further embodiment is the compound of Formula (Ia) wherein each ofR¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (Ia) wherein each ofR⁹ and R¹⁰ is independently hydrogen, halogen, alkyl or —OR⁶, wherein R⁶is hydrogen or alkyl.

In a further embodiment is the compound of Formula (Ia) wherein R⁵ isC₅-C₉ alkyl, aralkyl, or carbocyclylalkyl.

In a further embodiment is the compound of Formula (Ia) wherein

-   each of R₁, R₂, R₃ and R₄ is hydrogen;-   each of R₉ and R₁₀ is independently hydrogen or —OR₆, wherein R₆ is    hydrogen or alkyl; and-   R₅ is C₅-C₉ alkyl.

In a further embodiment is the compound of Formula (Ia) wherein R⁵ isC₅-C₉ alkyl substituted with —OR⁶, wherein

-   R⁶ is hydrogen or alkyl.

In a further embodiment is the compound of Formula (Ia) wherein

-   each of R¹, R², R³ and R⁴ is hydrogen;-   each of R⁹ and R¹⁰ is independently hydrogen or —OR⁶, wherein R⁶ is    hydrogen or alkyl; and-   R⁵ is aralkyl.

In a further embodiment is the compound of Formula (Ia) wherein

-   each of R¹, R², R³ and R⁴ is hydrogen;-   each of R⁹ and R¹⁰ is independently hydrogen or —OR⁶, wherein R⁶ is    hydrogen or alkyl; and-   R⁵ is carbocyclylalkyl.

In another embodiment is the compound of Formula (I) having a structureof Formula (Ib):

-   as a tautomer or a mixture of tautomers, or as a pharmaceutically    acceptable salt, hydrate, solvate, N-oxide or prodrug thereof,    wherein:-   R¹ and R² are each the same or different and independently hydrogen,    C₁-C₅ alkyl, or fluoroalkyl;-   R³ and R⁴ are each the same or different and independently hydrogen    or alkyl;-   R⁵ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or    carbocyclylalkyl;-   R¹¹ and R¹² are each the same or different and independently    hydrogen, alkyl, or —C(═O)R¹³; or-   R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and R¹³ is alkyl, alkenyl, aryl,    carbocyclyl, heteroaryl or heterocyclyl.

In another embodiment is the compound of Formula (Ib) wherein R¹¹ andR¹² is hydrogen.

In another embodiment is the compound of Formula (Ib) wherein each of R³and R⁴ is hydrogen.

In another embodiment is the compound of Formula (Ib) wherein

-   each of R¹, R², R³ and R⁴ is hydrogen, and-   R⁵ is C₅-C₉ alkyl, carbocyclylalkyl, heteroarylalkyl, or    heterocyclylalkyl.

In a further embodiment is the compound of Formula (I) selected from thegroup consisting of:

-   3-(3-pentylphenyl)propan-1-amine;-   3-(3-hexylphenyl)propan-1-amine;-   3-(3-(3,3-dimethylbutyl)phenyl)propan-1-amine;-   3-(3-(octan-4-yl)phenyl)propan-1-amine;-   4-(3-(3-aminopropyl)phenyl)butan-1-ol;-   6-(3-(3-aminopropyl)phenyl)hexan-1-ol;-   3-(3-(6-methoxyhexyl)phenyl)propan-1-amine;-   4-(3-(3-aminopropyl)phenethyl)heptan-4-ol;-   1-(3-(3-aminopropyl)phenyl)-3-ethylpentan-3-ol;-   4-(3-(3-aminopropyl)phenyl)-2-methylbutan-2-ol;-   3-(3-(3-aminopropyl)phenyl)propan-1-ol;-   3-(3-(3-methoxypropyl)phenyl)propan-1-amine;-   1-(3-(3-aminopropyl)phenyl)hexan-3-ol;-   4-(3-(3-amino-1-hydroxypropyl)phenethyl)heptan-4-ol;-   3-(3-(2,6-dimethylphenethyl)phenyl)propan-1-amine;-   3-(3-phenethylphenyl)propan-1-amine;-   3-(3-(3-phenylpropyl)phenyl)propan-1-amine;-   3-amino-1-(3-(3-phenylpropyl)phenyl)propan-1-ol;-   3-(3-(2-methylphenethyl)phenyl)propan-1-amine;-   3-(3-(2-(biphenyl-3-yl)ethyl)phenyl)propan-1-amine;-   3-(3-(4-phenylbutyl)phenyl)propan-1-amine;-   3-(3-(2-(naphthalen-2-yl)ethyl)phenyl)propan-1-amine;-   3-(3-(2-cyclohexylethyl)phenyl)propan-1-amine;-   3-(3-(2-cyclopentylethyl)phenyl)propan-1-amine;-   3-amino-1-(3-(2-cyclopentylethyl)phenyl)propan-1-ol;-   1-(3-(3-aminopropyl)phenethyl)cyclohexanol;-   1-(3-(3-amino-1-hydroxypropyl)phenethyl)cyclohexanol;-   1-(3-(3-aminopropyl)phenethyl)cycloheptanol;-   1-(3-(3-amino-1-hydroxypropyl)phenethyl)cycloheptanol;-   4-(3-(2-aminoethoxy)phenethyl)heptan-4-ol;-   1-(3-(2-aminoethoxy)phenethyl)cyclohexanol;-   1-(3-(2-aminoethoxy)phenethyl)cycloheptanol;-   4-(3-(2-aminoethoxy)phenethyl)tetrahydro-2H-thiopyran-4-ol;-   6-(3-(2-aminoethoxy)phenyl)hexan-1-ol;-   2-(3-(3-cyclopentylpropyl)phenoxy)ethanamine;-   2-(3-(2-(pyridin-3-yl)ethyl)phenoxy)ethanamine;-   2-(3-(2-(pyridin-2-yl)ethyl)phenoxy)ethanamine; and-   2-(3-(2-(thiophen-2-yl)ethyl)phenoxy)ethanamine.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—S—R⁴⁰, —C(R⁴²)₂—SO—R⁴⁰,    —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰, —C(R⁴²)₂—N(R⁴²)—R⁴⁰,    —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   R⁴² is selected from hydrogen or alkyl.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—S—R⁴⁰, —C(R⁴²)₂—SO—R⁴⁰,    —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰, —C(R⁴²)₂—N(R⁴²)—R⁴⁰,    —C(═O)—N(R⁴²)—R⁴⁰-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   R⁴² is selected from hydrogen or alkyl.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—S—R⁴⁰, —C(R⁴²)₂—SO—R⁴⁰,    —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰.

In another embodiment is the compound of Formula (B) wherein,

-   R⁴² is a hydrogen or C₁-C₃ alkyl; and-   R⁴⁰ is aryl or heteroaryl.

In another embodiment is the compound of Formula (B) wherein,

-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸);-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; and-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl.

In another embodiment is the compound of Formula (B) wherein,

-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸);-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl.

In an additional embodiment is the compound of Formula (A) wherein one,more than one, or all of the non-exchangeable ¹H atoms have beensubstituted with ²H atoms.

In a further embodiment is the compound of Formula (A) selected from thegroup consisting of:

In one embodiment is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (A) ortautomer, stereoisomer, geometric isomer, or pharmaceutically acceptablesolvate, hydrate, salt, N-oxide or prodrug thereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from —C(R⁴¹)₂ (R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸    and R²⁹ is independently selected from hydrogen, alkyl, alkenyl,    fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; with the provision that G is    not an unsubstituted normal alkyl and the provision that the    compound of Formula A is not:

In an additional embodiment is a non-retinoid compound that inhibits anisomerase reaction resulting in production of 11-cis retinol, whereinsaid isomerase reaction occurs in RPE, and wherein said compound has anED₅₀ value of 1 mg/kg or less when administered to a subject. In afurther embodiment is the non-retinoid compound wherein the ED₅₀ valueis measured after administering a single dose of the compound to saidsubject for about 2 hours or longer. In a further embodiment is thenon-retinoid compound, wherein the non-retinoid compound is an alkoxylcompound. In an additional embodiment is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a non-retinoidcompound as described herein. In an additional embodiment is a methodfor treating an ophthalmic disease or disorder in a subject, comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound asdescribed herein.

In an additional embodiment is a compound that inhibits 11-cis-retinolproduction with an IC₅₀ of about 1 μM or less when assayed in vitro,utilizing extract of cells that express RPE65 and LRAT, wherein theextract further comprises CRALBP, wherein the compound is stable insolution for at least about 1 week at room temperature. In a furtherembodiment, the compound inhibits 11-cis-retinol production with an IC₅₀of about 0.1 μM or less. In a further embodiment, the compound inhibits11-cis-retinol production with an IC₅₀ of about 0.01 μM or less. In afurther embodiment, the compound that inhibits 11-cis-retinol productionis a non-retinoid compound. In an additional embodiment is apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound that inhibits 11-cis-retinol production asdescribed herein. In an additional embodiment is a method for treatingan ophthalmic disease or disorder in a subject, comprising administeringto the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In an additionalembodiment is a method of modulating chromophore flux in a retinoidcycle comprising introducing into a subject a compound that inhibits11-cis-retinol production as described herein.

In an additional embodiment is a method for treating an ophthalmicdisease or disorder in a subject, comprising administering to thesubject a compound of Formula (G) or tautomer, stereoisomer, geometricisomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxideor prodrug thereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In an additional embodiment is a method of modulating chromophore fluxin a retinoid cycle comprising introducing into a subject a compound ofFormula (G). In a further embodiment is the method resulting in areduction of lipofuscin pigment accumulated in an eye of the subject. Ina further embodiment is the method resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject, wherein thelipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject. In a furtherembodiment is the method of treating an ophthalmic disease or disorderin a subject as described herein resulting in a reduction of lipofuscinpigment accumulated in an eye of the subject, wherein the lipofuscinpigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein, wherein the ophthalmicdisease or disorder is age-related macular degeneration or Stargardt'smacular dystrophy. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described herein, whereinthe ophthalmic disease or disorder is selected from retinal detachment,hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy,Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinaldisease, diabetic retinopathy, diabetic maculopathy, retinal bloodvessel occlusion, retinopathy of prematurity, or ischemia reperfusionrelated retinal injury, proliferative vitreoretinopathy, retinaldystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy,uveitis, a retinal injury, a retinal disorder associated withAlzheimer's disease, a retinal disorder associated with multiplesclerosis, a retinal disorder associated with Parkinson's disease, aretinal disorder associated with viral infection, a retinal disorderrelated to light overexposure, myopia, and a retinal disorder associatedwith AIDS. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described hereinresulting in a reduction of lipofuscin pigment accumulated in an eye ofthe subject. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described hereinresulting in a reduction of lipofuscin pigment accumulated in an eye ofthe subject, wherein the lipofuscin pigment isN-retinylidene-N-retinyl-ethanolamine (A2E).

In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound of Formula (G). In another embodiment is a method of inhibitingdark adaptation of a rod photoreceptor cell of the retina comprisingcontacting the retina with a non-retinoid compound as described herein.In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In another embodiment is a method of inhibiting regeneration ofrhodopsin in a rod photoreceptor cell of the retina comprisingcontacting the retina with a compound of Formula (G). In anotherembodiment is a method of inhibiting regeneration of rhodopsin in a rodphotoreceptor cell of the retina comprising contacting the retina with anon-retinoid compound as described herein. In another embodiment is amethod of inhibiting regeneration of rhodopsin in a rod photoreceptorcell of the retina comprising contacting the retina with a compound thatinhibits 11-cis-retinol production as described herein.

In another embodiment is a method of reducing ischemia in an eye of asubject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of Formula (G).

In an additional embodiment is a method of reducing ischemia in an eyeof a subject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and anon-retinoid compound as described herein. In an additional embodimentis a method of reducing ischemia in an eye of a subject comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In a further embodimentis the method of reducing ischemia in an eye of a subject, wherein thepharmaceutical composition is administered under conditions and at atime sufficient to inhibit dark adaptation of a rod photoreceptor cell,thereby reducing ischemia in the eye.

In an additional embodiment is a method of inhibiting neovascularizationin the retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a non-retinoid compound as described herein. Inan additional embodiment is a method of inhibiting neovascularization inthe retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound that inhibits 11-cis-retinolproduction as described herein. In a further embodiment is the method ofinhibiting neovascularization in the retina of an eye of a subject,wherein the pharmaceutical composition is administered under conditionsand at a time sufficient to inhibit dark adaptation of a rodphotoreceptor cell, thereby inhibiting neovascularization in the retina.

In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound of Formula (G). In an additional embodiment is a method ofinhibiting degeneration of a retinal cell in a retina comprisingcontacting the retina with a non-retinoid compound as described herein.In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In a further embodiment is the method of inhibiting degeneration of aretinal cell in a retina wherein the retinal cell is a retinal neuronalcell. In a further embodiment is the method of inhibiting degenerationof a retinal cell in a retina wherein the retinal neuronal cell is aphotoreceptor cell.

In another embodiment is a method of reducing lipofuscin pigmentaccumulated in a subject's retina comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of Formula (G). In an additionalembodiment is a method of reducing lipofuscin pigment accumulated in asubject's retina wherein the lipofuscin isN-retinylidene-N-retinyl-ethanolamine (A2E).

In an additional embodiment is a method of inhibiting reducinglipofuscin pigment accumulated in a subject's retina comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound asdescribed herein. In an additional embodiment is a method of reducinglipofuscin pigment accumulated in a subject's retina comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In an additionalembodiment is a method of reducing lipofuscin pigment accumulated in asubject's retina wherein the lipofuscin isN-retinylidene-N-retinyl-ethanolamine (A2E).

In an additional embodiment is a method of modulating chromophore fluxin a retinoid cycle comprising introducing into a subject a compound ofFormula (G) or tautomer, stereoisomer, geometric isomer or apharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrugthereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the method for treating an ophthalmic diseaseor disorder in a subject, comprising administering to the subject acompound of Formula (G), wherein the compound of Formula (G) is selectedfrom the group consisting of:

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 illustrates isomerase inhibitory activity of the compound ofExample 3 (Compound 3). The animals were orally gavaged with 1 mg/kgcompound, then “photo-bleached” (5000 Lux white light for 10 minutes) at4, 24 and 48 hours after dosing, and returned to darkness to allowrecovery of the 11-cis-retinal content of the eyes. Mice were sacrificed2 hours after bleaching, eyes were enucleated, and retinoid content wasanalyzed by HPLC.

FIGS. 2A and 2B illustrate concentration-dependent inhibition ofisomerase activity by the compound of Example 19 (Compound 19). FIG. 2Ashows concentration-dependent inhibition of 11-cis retinal (oxime)recovery. FIG. 2B shows the dose response (log dose, mg/ml) in which thedata are normalized to percent inhibition of isomerase activity.Inhibition of recovery was dose related, with the ED50 (dose of compoundthat gives 50% inhibition of 11-cis retinal (oxime) recovery) estimatedat 0.651 mg/kg. Five animals were included in each treatment group. Theerror bars correspond to standard error.

DETAILED DESCRIPTION OF THE INVENTION

Amine derivative compounds are described herein that inhibit anisomerization step of the retinoid cycle. These compounds andcompositions comprising these compounds are useful for inhibitingdegeneration of retinal cells or for enhancing retinal cell survival.The compounds described herein are, therefore, useful for treatingophthalmic diseases and disorders, including retinal diseases ordisorders, such as age related macular degeneration and Stargardt'sdisease.

I. AMINE DERIVATIVE COMPOUNDS

In certain embodiments, amine derivative compounds comprising ameta-substituted linkage terminating in a nitrogen-containing moiety areprovided. The nitrogen-containing moiety can be, for example, an amine,an amide or an N-heterocyclyl. The linkage comprises three linkingatoms, including at least two carbon atoms and up to one heteroatom,such as sulfur, oxygen and nitrogen. These linking atoms form acombination of linearly constructed stable chemical bonds, includingsingle, double or triple carbon-carbon bonds, carbon-nitrogen bonds,nitrogen-nitrogen bonds, carbon-oxygen bonds, carbon-sulfur bonds, andthe like.

Accordingly, in one embodiment, is a compound of Formula (A) ortautomer, stereoisomer, geometric isomer or a pharmaceuticallyacceptable solvate, hydrate, salt, N-oxide or prodrug thereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;    -   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,        carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or        SO₂NR²⁴R²⁵; or R⁷ and R⁸ together with the nitrogen atom to        which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; with the provision that G is    not an unsubstituted normal alkyl and the provision that the    compound of Formula A is not:

In another embodiment is the compound of Formula (A) wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or R¹¹ and    R¹², together with the nitrogen atom to which they are attached,    form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In another embodiment is the compound of Formula (A) having thestructure of Formula (B)

wherein,

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)— or —O—C(R³¹)(R³²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo; or optionally, R⁹ and R¹ together form a    direct bond to provide a double bond; or optionally, R⁹ and R¹    together form a direct bond, and R¹⁰ and R² together form a direct    bond to provide a triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹, and R³⁴ are each independently hydrogen or alkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl.

In another embodiment is the compound of Formula (B) wherein,

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)— or —O—C(R³¹)(R³²)—;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹, and R³⁴ are each independently hydrogen or alkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo.

In another embodiment is the compound of Formula (B) having thestructure of Formula (C)

wherein,

-   Z is —C(R⁹)(R¹⁰)—C(R¹)(R²)— or —O—C(R³¹)(R³²)—;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo; or optionally, R⁹ and R¹ together form a    direct bond to provide a double bond; or optionally, R⁹ and R¹    together form a direct bond, and R¹⁰ and R² together form a direct    bond to provide a triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹, and R³⁴ are each independently hydrogen or alkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl.

In another embodiment is the compound of Formula (C) wherein,

-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo.

In another embodiment is the compound of Formula (C) having thestructure of Formula (D):

wherein,

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R¹³; or R⁷ and R⁸, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    together form an oxo;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl or —C(═O)R²³; or R¹¹ and R¹², together with the nitrogen    atom to which they are attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl, alkenyl,    aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;-   R⁶, R¹⁹ and R³⁴ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²²; or R²⁰ and R²¹, together with the nitrogen    atom to which they are attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    to which they are attached form a carbocyclyl or heterocycle;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; and-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl.

In another embodiment is the compound of Formula (D) wherein n is 0 andeach of R¹¹ and R¹² is hydrogen. in a further embodiment is the compoundwherein each of R³, R⁴, R¹⁴ and R¹⁵ is hydrogen. In a further embodimentis the compound wherein,

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle; and-   R¹⁸ is selected from a hydrogen, alkoxy or hydroxy.

In a further embodiment is the compound wherein R¹⁶ and R¹⁷, togetherwith the carbon to which they are attached, form a cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and R¹⁸is hydrogen or hydroxy.

In another embodiment is the compound of Formula (D), wherein R¹¹ ishydrogen and R¹² is —C(═O)R²³, wherein R²³ is alkyl.

In a further embodiment is the compound of Formula (D), wherein

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or —OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy or alkoxy.

In a further embodiment is the compound of Formula (D) wherein,

-   n is 0;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a cyclopentyl, cyclohexyl or cyclohexyl; and-   R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (D) wherein,

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl or —OR⁶;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, or OR¹⁹; or R⁹ and R¹⁰ together form an oxo;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷ is independently selected from C₁-C₁₃ alkyl; and-   R¹⁸ is hydrogen, hydroxy or alkoxy.

In another embodiment is the compound of Formula (C) having thestructure of Formula (E):

wherein,

-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, or —C(═O)R²³; or R¹¹ and R¹², together with the    nitrogen atom to which they are attached, form an N-heterocyclyl;-   R²³ is selected from alkyl, alkenyl, aryl, carbocyclyl, heteroaryl    or heterocyclyl;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen or alkyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    atom to which they are attached, form a carbocyclyl or heterocycle;-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   R³⁴ is hydrogen or alkyl; and-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In another embodiment is the compound of Formula (E) wherein n is 0 andeach of R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (E) wherein each R³,R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (E) wherein,

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl; and-   R¹⁸ is hydrogen, hydroxy, or alkoxy.

In a further embodiment is the compound of Formula (E) wherein R¹⁶ andR¹⁷, together with the carbon atom to which they are attached form acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (E) wherein, R³¹ andR³² are each independently selected from hydrogen, or C₁-C₅ alkyl; andR¹⁸ is hydrogen, hydroxy or alkoxy.

In a further embodiment is the compound of Formula (E) wherein,

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R⁶ and R¹⁹ are each independently hydrogen or alkyl;-   R¹⁶ and R¹⁷ is independently selected from C₁-C₁₃ alkyl; and-   R¹⁸ is hydrogen, hydroxy or alkoxy.

In another embodiment is the compound of Formula (A) wherein,

-   Z is a bond, —X—C(R³¹)(R³²)—, or —X—C(R³¹)(R³²)—C(R¹)(R²)—; and-   X is —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—.

In a further embodiment is the compound of Formula (A) wherein,

-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo.

In another embodiment is the compound of Formula (A) having thestructure of Formula (F):

wherein,

-   X is —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³ and R⁴ are each independently selected from hydrogen or alkyl; or    R³ and R⁴ together form an imino;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, or —C(═O)R²³; or R¹¹ and R¹², together with the    nitrogen atom to which they are attached, form an N-heterocyclyl;-   R²³ is selected from alkyl, alkenyl, aryl, carbocyclyl, heteroaryl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁-C₁₃    alkyl, halo or fluoroalkyl; or R¹⁶ and R¹⁷, together with the carbon    atom to which they are attached, form a carbocyclyl or heterocycle;-   R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R¹⁸ is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the compound of Formula (F) wherein n is 0and each R¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (F) wherein each R³,R⁴, R¹⁴ and R¹⁵ is hydrogen.

In a further embodiment is the compound of Formula (F) wherein,

-   R³¹ and R³² are each independently hydrogen, or C₁-C₅ alkyl;-   R¹⁶ and R¹⁷, together with the carbon atom to which they are    attached, form a carbocyclyl or heterocycle; and-   R¹⁸ is hydrogen, hydroxy, or alkoxy.

In a further embodiment is the compound of Formula (F) wherein R¹⁶ andR¹⁷, together with the carbon atom to which they are attached form acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl and R¹⁸ is hydrogen or hydroxy.

In a further embodiment is the compound of Formula (F) wherein, R³¹ andR³² are each independently selected from hydrogen, or C₁-C₅ alkyl; R¹⁶and R¹⁷ is independently selected from C₁-C₁₃ alkyl; and R¹⁸ ishydrogen, hydroxy or alkoxy.

In one embodiment is a compound having a structure of Formula (I):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:

-   R¹ and R² are each the same or different and independently hydrogen,    halogen, C₁-C₅ alkyl, fluoroalkyl, —OR⁶, or —NR⁷R; or R¹ and R² form    an oxo;-   R³ and R⁴ are each the same or different and independently hydrogen    or alkyl;-   R⁵ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or    carbocyclylalkyl;-   R⁶ is hydrogen or alkyl;-   R⁷ and R⁸ are each the same or different and independently hydrogen,    alkyl, carbocyclyl, or —C(═O)R¹³; or-   R⁷ and R⁸, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is —C(R⁹)(R¹⁰)— or —O—;-   R⁹ and R¹⁰ are each the same or different and independently    hydrogen, halogen, alkyl, fluoroalkyl, —OR⁶, —NR⁷R⁸ or carbocyclyl;    or R⁹ and R¹⁰ form an oxo;-   R¹¹ and R¹² are each the same or different and independently    hydrogen, alkyl, or —C(═O)R¹³; or-   R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   R¹³ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or    heterocyclyl.

In another embodiment is the compound of Formula (I) having a structureof Formula (Ia):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:

-   R¹ and R² are each the same or different and independently hydrogen,    halogen, C₁-C₅ alkyl, fluoroalkyl, —OR⁶, or —NR⁷R⁸; or R¹ and R²    form an oxo;-   R³ and R⁴ are each the same or different and independently hydrogen    or alkyl;-   R⁵ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or    carbocyclylalkyl;-   R⁶ is hydrogen or alkyl;-   R⁷ and R⁸ are each the same or different and independently hydrogen,    alkyl, carbocyclyl, or —C(═O)R¹³; or-   R⁷ and R⁸, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each the same or different and independently    hydrogen, halogen, alkyl, fluoroalkyl, —OR⁶, —NR⁷R⁸ or carbocyclyl;    or R⁹ and R¹⁰ form an oxo;-   R¹¹ and R¹² are each the same or different and independently    hydrogen, alkyl, or —C(═O)R¹³; or-   R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   R¹³ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or    heterocyclyl.

In a further embodiment is the compound of Formula (Ia) wherein each ofR¹¹ and R¹² is hydrogen.

In a further embodiment is the compound of Formula (Ia) wherein each ofR⁹ and R¹⁰ is independently hydrogen, halogen, alkyl or OR⁶, wherein R⁶is hydrogen or alkyl.

In a further embodiment is the compound of Formula (Ia) wherein R⁵ isC₅-C₉ alkyl, aralkyl, or carbocyclylalkyl.

In a further embodiment is the compound of Formula (Ia) wherein

-   each of R₁, R₂, R₃ and R₄ is hydrogen;-   each of R₉ and R₁₀ is independently hydrogen or —OR₆, wherein R₆ is    hydrogen or alkyl; and-   R₅ is C₅-C₉ alkyl.

In a further embodiment is the compound of Formula (Ia) wherein R⁵ isC₅-C₉ alkyl substituted with —OR⁶, wherein

-   R⁶ is hydrogen or alkyl.

In a further embodiment is the compound of Formula (Ia) wherein

-   each of R¹, R², R³ and R⁴ is hydrogen;-   each of R⁹ and R¹⁰ is independently hydrogen or —OR⁶, wherein R⁶ is    hydrogen or alkyl; and-   R⁵ is aralkyl.

In a further embodiment is the compound of Formula (Ia) wherein

-   each of R¹, R², R³ and R⁴ is hydrogen;-   each of R⁹ and R¹⁰ is independently hydrogen or —OR⁶, wherein R⁶ is    hydrogen or alkyl; and-   R⁵ is carbocyclylalkyl.

In another embodiment is the compound of Formula (I) having a structureof Formula (Ib):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:

-   R¹ and R² are each the same or different and independently hydrogen,    C₁-C₅ alkyl, or fluoroalkyl;-   R³ and R⁴ are each the same or different and independently hydrogen    or alkyl;-   R⁵ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or    carbocyclylalkyl;-   R¹¹ and R¹² are each the same or different and independently    hydrogen, alkyl, or —C(═O)R¹³; or-   R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and R¹³ is alkyl, alkenyl, aryl,    carbocyclyl, heteroaryl or heterocyclyl.

In another embodiment is the compound of Formula (Ib) wherein R¹¹ andR¹² is hydrogen.

In another embodiment is the compound of Formula (Ib) wherein each of R³and R⁴ is hydrogen.

In another embodiment is the compound of Formula (Ib) wherein

-   each of R¹, R², R³ and R⁴ is hydrogen, and-   R⁵ is C₅-C₉ alkyl, carbocyclylalkyl, heteroarylalkyl, or    heterocyclylalkyl.

In a further embodiment is the compound of Formula (I) selected from thegroup consisting of:

-   3-(3-pentylphenyl)propan-1-amine;-   3-(3-hexylphenyl)propan-1-amine;-   3-(3-(3,3-dimethylbutyl)phenyl)propan-1-amine;-   3-(3-(octan-4-yl)phenyl)propan-1-amine;-   4-(3-(3-aminopropyl)phenyl)butan-1-ol;-   6-(3-(3-aminopropyl)phenyl)hexan-1-ol;-   3-(3-(6-methoxyhexyl)phenyl)propan-1-amine;-   4-(3-(3-aminopropyl)phenethyl)heptan-4-ol;-   1-(3-(3-aminopropyl)phenyl)-3-ethylpentan-3-ol;-   4-(3-(3-aminopropyl)phenyl)-2-methylbutan-2-ol;-   3-(3-(3-aminopropyl)phenyl)propan-1-ol;-   3-(3-(3-methoxypropyl)phenyl)propan-1-amine;-   1-(3-(3-aminopropyl)phenyl)hexan-3-ol;-   4-(3-(3-amino-1-hydroxypropyl)phenethyl)heptan-4-ol;-   3-(3-(2,6-dimethylphenethyl)phenyl)propan-1-amine;-   3-(3-phenethylphenyl)propan-1-amine;-   3-(3-(3-phenylpropyl)phenyl)propan-1-amine;-   3-amino-1-(3-(3-phenylpropyl)phenyl)propan-1-ol;-   3-(3-(2-methylphenethyl)phenyl)propan-1-amine;-   3-(3-(2-(biphenyl-3-yl)ethyl)phenyl)propan-1-amine;-   3-(3-(4-phenylbutyl)phenyl)propan-1-amine;-   3-(3-(2-(naphthalen-2-yl)ethyl)phenyl)propan-1-amine;-   3-(3-(2-cyclohexylethyl)phenyl)propan-1-amine;-   3-(3-(2-cyclopentylethyl)phenyl)propan-1-amine;-   3-amino-1-(3-(2-cyclopentylethyl)phenyl)propan-1-ol;-   1-(3-(3-aminopropyl)phenethyl)cyclohexanol;-   1-(3-(3-amino-1-hydroxypropyl)phenethyl)cyclohexanol;-   1-(3-(3-aminopropyl)phenethyl)cycloheptanol;-   1-(3-(3-amino-1-hydroxypropyl)phenethyl)cycloheptanol;-   4-(3-(2-aminoethoxy)phenethyl)heptan-4-ol;-   1-(3-(2-aminoethoxy)phenethyl)cyclohexanol;-   1-(3-(2-aminoethoxy)phenethyl)cycloheptanol;-   4-(3-(2-aminoethoxy)phenethyl)tetrahydro-2H-thiopyran-4-ol;-   6-(3-(2-aminoethoxy)phenyl)hexan-1-ol;-   2-(3-(3-cyclopentylpropyl)phenoxy)ethanamine;-   2-(3-(2-(pyridin-3-yl)ethyl)phenoxy)ethanamine;-   2-(3-(2-(pyridin-2-yl)ethyl)phenoxy)ethanamine; and-   2-(3-(2-(thiophen-2-yl)ethyl)phenoxy)ethanamine.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—S—R⁴⁰, —C(R⁴²)₂—SO—R⁴⁰,    —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰, —C(R⁴²)₂—N(R⁴²)—R⁴⁰,    —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   R⁴² is selected from hydrogen or alkyl.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—S—R⁴⁰, —C(R⁴²)₂—SO—R⁴⁰,    —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰, —C(R⁴²)₂—N(R⁴²)—R⁴⁰,    —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   R⁴² is selected from hydrogen or alkyl.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—S—R⁴⁰, —C(R⁴²)₂—SO—R⁴⁰,    —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰.

In another embodiment is the compound of Formula (B) wherein,

-   G is selected from —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰.

In another embodiment is the compound of Formula (B) wherein,

-   R⁴² is a hydrogen or C₁-C₃ alkyl; and-   R⁴⁰ is aryl or heteroaryl.

In another embodiment is the compound of Formula (B) wherein,

-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸);-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; and-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl.

In another embodiment is the compound of Formula (B) wherein,

-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸);-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl.

In an additional embodiment is the compound of Formula (A) wherein one,more than one, or all of the non-exchangeable ¹H atoms have beensubstituted with ²H atoms.

In a further embodiment is the compound of Formula (A) selected from thegroup consisting of:

In one embodiment is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (A) ortautomer, stereoisomer, geometric isomer, or pharmaceutically aceptablesolvate, hydrate, salt, N-oxide or prodrug thereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from C(R¹⁶)(R¹)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; with the provision that G is    not an unsubstituted normal alkyl and the provision that the    compound of Formula A is not:

In an additional embodiment is a non-retinoid compound that inhibits anisomerase reaction resulting in production of 11-cis retinol, whereinsaid isomerase reaction occurs in RPE, and wherein said compound has anED50 value of 1 mg/kg or less when administered to a subject. In afurther embodiment is the non-retinoid compound wherein the ED50 valueis measured after administering a single dose of the compound to saidsubject for about 2 hours or longer. In a further embodiment is thenon-retinoid compound, wherein the non-retinoid compound is an alkoxylcompound. In an additional embodiment is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a non-retinoidcompound as described herein. In an additional embodiment is a methodfor treating an ophthalmic disease or disorder in a subject, comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound asdescribed herein.

In an additional embodiment is a compound that inhibits 11-cis-retinolproduction with an IC₅₀ of about 1 μM or less when assayed in vitro,utilizing extract of cells that express RPE65 and LRAT, wherein theextract further comprises CRALBP, wherein the compound is stable insolution for at least about 1 week at room temperature. In a furtherembodiment, the compound inhibits 11-cis-retinol production with an IC₅₀of about 0.1 μM or less. In a further embodiment, the compound inhibits11-cis-retinol production with an IC₅₀ of about 0.01 μM or less. In afurther embodiment, the compound that inhibits 11-cis-retinol productionis a non-retinoid compound. In an additional embodiment is apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound that inhibits 11-cis-retinol production asdescribed herein. In an additional embodiment is a method for treatingan ophthalmic disease or disorder in a subject, comprising administeringto the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In an additionalembodiment is a method of modulating chromophore flux in a retinoidcycle comprising introducing into a subject a compound that inhibits11-cis-retinol production as described herein.

In an additional embodiment is a method for treating an ophthalmicdisease or disorder in a subject, comprising administering to thesubject a compound of Formula (G) or tautomer, stereoisomer, geometricisomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxideor prodrug thereof:

wherein,

-   -   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—,        —X—C(R³¹)(R³²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or        —X—C(R³¹)(R³²)—C(R¹)(R²)—;

-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;

-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;

-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;

-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;

-   each R⁴² is independently selected from hydrogen or alkyl;

-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or NR⁷R⁸; or R¹ and R² together form    an oxo;

-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;

-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;

-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;

-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;

-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;

-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;

-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;

-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;

-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;

-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and

-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;

-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;

-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;

-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In an additional embodiment is a method of modulating chromophore fluxin a retinoid cycle comprising introducing into a subject a compound ofFormula (G). In a further embodiment is the method resulting in areduction of lipofuscin pigment accumulated in an eye of the subject. Ina further embodiment is the method resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject, wherein thelipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject. In a furtherembodiment is the method of treating an ophthalmic disease or disorderin a subject as described herein resulting in a reduction of lipofuscinpigment accumulated in an eye of the subject, wherein the lipofuscinpigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein, wherein the ophthalmicdisease or disorder is age-related macular degeneration or Stargardt'smacular dystrophy. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described herein, whereinthe ophthalmic disease or disorder is selected from retinal detachment,hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy,Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinaldisease, diabetic retinopathy, diabetic maculopathy, retinal bloodvessel occlusion, retinopathy of prematurity, or ischemia reperfusionrelated retinal injury, proliferative vitreoretinopathy, retinaldystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy,uveitis, a retinal injury, a retinal disorder associated withAlzheimer's disease, a retinal disorder associated with multiplesclerosis, a retinal disorder associated with Parkinson's disease, aretinal disorder associated with viral infection, a retinal disorderrelated to light overexposure, myopia, and a retinal disorder associatedwith AIDS. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described hereinresulting in a reduction of lipofuscin pigment accumulated in an eye ofthe subject. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described hereinresulting in a reduction of lipofuscin pigment accumulated in an eye ofthe subject, wherein the lipofuscin pigment isN-retinylidene-N-retinyl-ethanolamine (A2E).

In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound of Formula (G). In another embodiment is a method of inhibitingdark adaptation of a rod photoreceptor cell of the retina comprisingcontacting the retina with a non-retinoid compound as described herein.In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In another embodiment is a method of inhibiting regeneration ofrhodopsin in a rod photoreceptor cell of the retina comprisingcontacting the retina with a compound of Formula (G). In anotherembodiment is a method of inhibiting regeneration of rhodopsin in a rodphotoreceptor cell of the retina comprising contacting the retina with anon-retinoid compound as described herein. In another embodiment is amethod of inhibiting regeneration of rhodopsin in a rod photoreceptorcell of the retina comprising contacting the retina with a compound thatinhibits 11-cis-retinol production as described herein.

In another embodiment is a method of reducing ischemia in an eye of asubject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of Formula (G).

In an additional embodiment is a method of reducing ischemia in an eyeof a subject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and anon-retinoid compound as described herein. In an additional embodimentis a method of reducing ischemia in an eye of a subject comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In a further embodimentis the method of reducing ischemia in an eye of a subject, wherein thepharmaceutical composition is administered under conditions and at atime sufficient to inhibit dark adaptation of a rod photoreceptor cell,thereby reducing ischemia in the eye.

In an additional embodiment is a method of inhibiting neovascularizationin the retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a non-retinoid compound as described herein. Inan additional embodiment is a method of inhibiting neovascularization inthe retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound that inhibits 11-cis-retinolproduction as described herein. In a further embodiment is the method ofinhibiting neovascularization in the retina of an eye of a subject,wherein the pharmaceutical composition is administered under conditionsand at a time sufficient to inhibit dark adaptation of a rodphotoreceptor cell, thereby inhibiting neovascularization in the retina.

In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound of Formula (G). In an additional embodiment is a method ofinhibiting degeneration of a retinal cell in a retina comprisingcontacting the retina with a non-retinoid compound as described herein.In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In a further embodiment is the method of inhibiting degeneration of aretinal cell in a retina wherein the retinal cell is a retinal neuronalcell. In a further embodiment is the method of inhibiting degenerationof a retinal cell in a retina wherein the retinal neuronal cell is aphotoreceptor cell.

In another embodiment is a method of reducing lipofuscin pigmentaccumulated in a subject's retina comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of Formula (G). In an additionalembodiment is a method of reducing lipofuscin pigment accumulated in asubject's retina wherein the lipofuscin isN-retinylidene-N-retinyl-ethanolamine (A2E).

In an additional embodiment is a method of inhibiting reducinglipofuscin pigment accumulated in a subject's retina comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound asdescribed herein. In an additional embodiment is a method of reducinglipofuscin pigment accumulated in a subject's retina comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In an additionalembodiment is a method of reducing lipofuscin pigment accumulated in asubject's retina wherein the lipofuscin isN-retinylidene-N-retinyl-ethanolamine (A2E).

In an additional embodiment is a method of modulating chromophore fluxin a retinoid cycle comprising introducing into a subject a compound ofFormula (G) or tautomer, stereoisomer, geometric isomer or apharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrugthereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the method for treating an ophthalmic diseaseor disorder in a subject, comprising administering to the subject acompound of Formula (G), wherein the compound of Formula (G) is selectedfrom the group consisting of:

In certain embodiments, amine derivative compounds comprising ameta-substituted linkage terminating in a nitrogen-containing moiety areprovided. The nitrogen-containing moiety can be, for example, an amine,an amide or an N-heterocyclyl. The linkage comprises three linkingatoms, including at least two carbon atoms and up to one heteroatom,such as sulfur, oxygen and nitrogen. These linking atoms form acombination of linearly constructed stable chemical bonds, includingsingle, double or triple carbon-carbon bonds, carbon-nitrogen bonds,nitrogen-nitrogen bonds, carbon-oxygen bonds, carbon-sulfur bonds, andthe like.

Thus, the compounds can be represented by Formula (I)

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:

-   R₁ and R₂ are each the same or different and independently hydrogen,    halogen, C₁-C₅ alkyl, fluoroalkyl, —OR₆ or —NR₇R₈; or-   R₁ and R₂ form an oxo;-   R₃ and R₄ are each the same or different and independently hydrogen    or alkyl;-   R₅ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or    carbocyclylalkyl;-   R₆ is hydrogen or alkyl;-   R₇ and R₈ are each the same or different and independently hydrogen,    alkyl, carbocyclyl, or —C(═O)R₁₃; or-   R₇ and R₈, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   X is C(R₉)(R₁₀)— or —O—;-   R₉ and R₁₀ are each the same or different and independently    hydrogen, halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl;    or-   R₉ and R₁₀ form an oxo;-   R₁₁ and R₁₂ are each the same or different and independently    hydrogen, alkyl, or —C(═O)R₁₃; or-   R₁₁ and R₁₂, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   R₁₃ is alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl.

In certain embodiments, each of R₁₁ and R₁₂ is hydrogen.

In other embodiments, R₁₁ is hydrogen and R₁₂ is —C(═O)R₁₃, wherein R₁₃is alkyl.

In certain embodiments, each of R₃ and R₄ is hydrogen.

In other certain embodiments, R₁ and R₂ are each independently hydrogen,halogen, C₁-C₅ alkyl or —OR₆, wherein R₆ is hydrogen or alkyl.

In other embodiments, R₉ and R₁₀ are each independently hydrogen,halogen, alkyl or —OR₆, wherein R₆ is hydrogen or alkyl.

In another specific embodiment, each of R₁, R₂, R₉ and R₁₀ isindependently hydrogen or —OR₆, wherein R₆ is hydrogen or alkyl.

In a specific embodiment, R₉ and R₁₀ together form oxo.

In certain other embodiments, R₅ is C₅-C₉ alkyl.

In yet other embodiments, R₅ is aralkyl.

In other embodiments, R₅ is heteroarylalkyl.

In still other embodiments, R₅ is heterocyclylalkyl.

In certain other embodiments, R₅ is carbocyclylalkyl.

In one embodiment, X is —C(R₉)(R₁₀)—, and the compound of Formula (I)can be represented by a structure of Formula (Ia):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:

-   -   R₁ and R₂ are each the same or different and independently        hydrogen, halogen, C₁-C₅ alkyl, fluoroalkyl, —OR₆, or —NR₇R⁸; or

-   R₁ and R₂ form an oxo;

-   R₃ and R₄ are each the same or different and independently hydrogen    or alkyl;

-   R₅ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, or    carbocyclylalkyl;

-   R₆ is hydrogen or alkyl;

-   R₇ and R₈ are each the same or different and independently hydrogen,    alkyl, carbocyclyl, or —C(═O)R₁₃; or

-   R₇ and R₈, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;

-   R₉ and R₁₀ are each the same or different and independently    hydrogen, halogen, alkyl, fluoroalkyl, —OR₆, —NR₇R₈ or carbocyclyl;    or

-   R₉ and R₁₀ form an oxo;

-   R₁₁ and R₁₂ are each the same or different and independently    hydrogen, alkyl, or —C(═O)R₁₃; or

-   R₁₁ and R₁₂, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and

-   R₁₃ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl, or    heterocyclyl.

In certain embodiments of the compound having a structure represented byFormula (Ia), each of R₁₁ and R₁₂ is hydrogen.

In other embodiments, R₁₁ is hydrogen and R₁₂ is —C(═O)R₁₃, wherein R₁₃is alkyl.

In other embodiments, each of R₃ and R₄ is hydrogen.

In a specific embodiment, each of R₉ and R₁₀ is independently hydrogen,halogen, alkyl or —OR₆, wherein R₆ is hydrogen or alkyl.

In certain embodiments, R₅ is C₅-C₉ alkyl.

In other certain embodiments, R₅ is aralkyl.

In still other certain embodiments, R₅ is carbocyclylalkyl.

In further embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₃ and R₄ is hydrogen, each of R₉ and R₁₀ is independently hydrogen or—OR₆, wherein R₆ is hydrogen or alkyl, and R₅ is C₅-C₉ alkyl.

In certain specific embodiments, R₅ is C₅-C₉ alkyl substituted with—OR₆, wherein R₆ is hydrogen or alkyl.

Certain compounds disclosed herein have the structures shown in Table 1.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 1 Example Number Structure Name 27

3-(3-pentylphenyl)propan-1-amine 28

3-(3-hexylphenyl)propan-1-amine 29

3-(3-(3,3-dimethylbutyl)phenyl)propan-1- amine 34

3-(3-(octan-4-yl)phenyl)propan-1-amine 23

4-(3-(3-aminopropyl)phenyl)butan-1-ol 30

6-(3-(3-aminopropyl)phenyl)hexan-1-ol 33

3-(3-(6-methoxyhexyl)phenyl)propan-1- amine 3

4-(3-(3-aminopropyl)phenethyl)heptan-4-ol 2

1-(3-(3-aminopropyl)phenyl)-3-ethylpentan- 3-ol 4

4-(3-(3-aminopropyl)phenyl)-2-methylbutan- 2-ol 6

3-(3-(3-aminopropyl)phenyl)propan-1-ol 5

3-(3-(3-methoxypropyl)phenyl)propan-1- amine 8

1-(3-(3-aminopropyl)phenyl)hexan-3-ol 19

4-(3-(3-amino-1- hydroxypropyl)phenethyl)heptan-4-ol 39

5-(3-(3-aminopropyl)phenethyl)nonan-5-ol 40

3-(3-(3-methoxy-3- propylhexyl)phenyl)propan-1-amine 41

1-(3-(3-aminopropyl)phenyl)-3-methylhexan- 3-ol 42

1-(3-(3-aminopropyl)phenyl)-3 ,5- dimethylhexan-3-ol 44

4-(3-(3-amino-2,2- dimethylpropyl)phenethyl)heptan-4-ol 45

1-(3-(3-aminopropyl)phenyl)-3,4- dimethylpentan-3-ol 46

4-(3-(3-aminopropyl)phenyl)-2-phenylbutan- 2-ol 47

1-(3-(3-aminopropyl)phenyl)-4- methylpentan-3-ol 49

1-(3-(3-aminopropyl)phenyl)-3,4,4- trimethylpentan-3-ol 55

1-(3-(3-aminopropyl)phenyl)-3-isopropyl-4- methylpentan-3-ol 56

4-(3-(3-aminopropyl)phenethyl)-2,6- dimethylheptan-4-ol 57

5-(3-(3-aminopropyl)phenyl)pentan-2-ol 59

6-(3-(3-amino-1- hydroxypropyl)phenyl)hexan-1-ol 60

4-(3-(3-amino-1- hydroxypropyl)phenyl)butan-1-ol 62

3-(3-(2-(thiophen-2-yl)ethyl)phenyl)propan- 1-amine 70

(S)-4-(3-(3-amino-1- hydroxypropyl)phenethyl)heptan-4-ol 71

(R)-4-(3-(3-amino-1- hydroxypropyl)phenethyl)heptan-4-ol 72

3-amino-1-(3-(3- methoxypropyl)phenyl)propan-1-ol 73

3-amino-1-(3-hexylphenyl)propan-1-ol 79

3-amino-1-(3-(3- hydroxypropyl)phenyl)propan-1-ol 80

1-(3-(3-amino-1- hydroxypropyl)phenyl)hexan-3-ol 82

3-amino-1-(3-(4- methoxybutyl)phenyl)propan-1-ol 86

5-(3-(3-amino-1-hydroxypropyl)phenyl)-N,N- dimethylpentanamide 87

5-(3-(3-aminopropyl)phenyl)pentan-1-ol 90

3-amino-1-(3-(4- methylpentyl)phenyl)propan-1-ol 91

5-(3-(3-amino-1- hydroxypropyl)phenyl)pentan-1-ol 92

3-(3-(4-methylpentyl)phenyl-propan-1-amine 97

5-(3-(3-aminopropyl)phenyl)-N,N- dimethylpentanamide 102

1-(3-(3-amino-1-hydroxypropyl)phenyl)-4- methylpentan-3-ol 104

5-(3-(3-amino-1- hydroxypropyl)phenyl)pentanamide 106

3-amino-1-(3-(5- methoxypentyl)phenyl)propan-1-ol 109

1-(3-(3-amino-1-hydroxypropyl)phenyl)-3- methylhexan-3-ol 110

3-amino-1-(3-(2-(tetrahydro-2H-pyran-2- yl)ethyl)phenyl)propan-1-ol 111

5-(3-(3-aminopropyl)phenyl)-N- methylpentanamide 112

5-(3-(3-aminopropyl)phenyl)pentanamide 113

1-(3-(3-amino-1-hydroxypropyl)phenyl)-3- ethylpentan-3-ol 116

3-(3-(3-aminopropyl)phenyl)-1- phenylpropan-1-ol 117

3-(3-(3-aminopropyl)phenyl)-2,2- dimethylpropyl acetate 118

3-(3-(3-aminopropyl)phenyl)-2,2- dimethylpropan-1-ol 119

2-(3-(3-aminopropyl)phenyl)decan-2-ol 120

2-(3-(3-aminopropyl)phenyl)hexan-2-ol 121

1-(3-(3-aminopropyl)phenyl)-2-methylhexan- 2-ol 122

3-(3-(4-methoxybutyl)phenyl)propan-1-amine 124

3-amino-1-(3-(3-hydroxy-3- phenylpropyl)phenyl)propan-1-ol 126

5-(3-(3-aminopropyl)phenyl)-N,N- dimethylpentanamide 132

(R)-3-(3-(3-aminopropyl)phenyl)-1- phenylpropan-1-ol 140

4-(5-(3-amino-1-hydroxypropyl)-2- fluorophenethyl)heptan-4-ol 141

(R)-N-(3-hydroxy-3-(3-(3-hydroxy-3- propylhexyl)phenyl)propyl)acetamide142

(R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3- hydroxy-3-propylhexyl)phenyl)propypacetamide 143

4-(3-(3-amino-2- hydroxypropyl)phenethyl)heptan-4-ol 144

4-(5-(3-amino-1-hydroxypropyl)-2- methoxyphenethyl)heptan-4-ol 145

4-(5-(3-amino-1-hydroxypropyl)-2- methylphenethyl)heptan-4-ol 146

4-(3-(3-amino-1-hydroxypropyl)-5- methoxyphenethyl)heptan-4-ol 147

4-(3-(3-amino-1-hydroxypropyl)-4- chlorophenethyl)heptan-4-ol 148

4-(3-(3-amino-1-hydroxypropyl)-4- methylphenethyl)heptan-4-ol 149

1-(3-(3-amino-2-hydroxypropyl)phenyl)-3- ethylpentan-3-ol 167

(R)-4-(3-(1-hydroxy-3- (methylamino)propyl)phenethyl)heptan-4-ol 161

4-(3-(aminomethyl)phenethyl)heptan-4-ol 168

1-(3-(3-hydroxy-3- propylhexyl)benzyl)guanidine 169

1-(3-(3-(3-hydroxy-3- propylhexyl)phenyl)propyl)guanidine 170

3-hydroxy-3-(3-(3-hydroxy-3- propylhexyl)phenyl)propanimidamide 171

1-amino-3-(3-(3-hydroxy-3- propylhexyl)phenyl)propan-2-one 172

4-(3-(3-amino-2- fluoropropyl)phenethyl)heptan-4-ol 173

3-amino-1-(3-(3-hydroxy-3 propylhexyl)phenyl)propan-1-one 174

4-(3-(3-amino-1- fluoropropyl)phenethyl)heptan-4-ol 175

4-(3-(4-aminobutan-2-yl)phenethypheptan- 4-ol 176

4-(3-(3-amino-1-hydroxypropyl)-5- chlorophenethyl)heptan-4-ol 177

(R)-3-(3-amino-1-hydroxypropyl)-N- (heptan-4-yl)benzamide 178

4-(3-(3-aminobutyl)phenethyl)heptan-4-ol

In further embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₃ and R₄ is hydrogen, and each of R₉ and R₁₀ is independently hydrogenor —OR₆, wherein R₆ is hydrogen or alkyl, and R₅ is aralkyl.

In certain specific embodiments, the alkylene portion of R₅ is ethylene,propylene, or butylene.

In certain embodiments, the aryl portion of R₅ is phenyl, tolyl,xylenyl, biphenyl, or naphthyl.

Certain compounds disclosed herein have the structures shown in Table 2.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 2 Example Number Structure Name 1

3-(3-(2,6-dimethylphenethyl)phenyl)propan-1- amine 22

3-(3-phenethylphenyl)propan-1-amine 26

3-(3-(3-phenylpropyl)phenyl)propan-1-amine 18

3-amino-1-(3-(3-phenylpropyl)phenyl)propan- 1-ol 31

3-(3-(2-methylphenethyl)phenyl)propan-1- amine 32

3-(3-(2-(biphenyl-3-yl)ethyl)phenyl)propan-1- amine 35

3-(3-(4-phenylbutyl)phenyl)propan-1-amine 21

3-(3-(2-(naphthalen-2-yl)ethyl)phenyl)propan- 1-amine 58

3-(3-(2-methoxyphenethyl)phenyl)propan-1- amine 61

3-amino-1-(3-(2- methoxyphenethyl)phenyl)propan-1-ol 63

3-amino-1-(3-(4-phenylbutyl)phenyl)propan- 1-ol 85

3-amino-1-(3-phenethylphenyl)propan-1-ol 138

(R)-3-amino-1-(3-(4- phenylbutyl)phenyl)propan-1-ol

In further embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₃ and R₄ is hydrogen, each of R₉ and R₁₀ is independently hydrogen or—OR₆, wherein R₆ is hydrogen or alkyl, and R₅ is carbocyclylalkyl. Incertain embodiments, the carbocyclylalkyl can be further substitutedwith —OR₆, wherein R₆ is hydrogen or alkyl.

In certain specific embodiments, the alkylene portion of R₅ is ethylene,propylene. or butylene.

In certain embodiments, the carbocyclyl portion of R₅ is cyclohexyl,cyclopentyl or cycloheptyl.

Certain compounds disclosed herein have the structures shown in Table 3.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 3 Example Number Structure Name 25

3-(3-(2- cyclohexylethyl)phenyl)propan-1- amine 24

3-(3-(2- cyclopentylethyl)phenyl)propan-1- amine 17

3-amino-1-(3-(2- cyclopentylethyl)phenyl)propan-1- ol 7

1-(3-(3- aminopropyl)phenethyl) cyclohexanol 15

1-(3-(3-amino-1- hydroxypropyl)phenethyl) cyclohexanol 20

1-(3-(3- aminopropyl)phenethyl) cycloheptanol 16

1-(3-(3-amino-1- hydroxypropyl)phenethyl) cycloheptanol 43

1-(3-(3-aminopropyl)phenethyl)- 2,2,6,6-tetramethylcyclohexanol 48

1-(3-(3- aminopropyl)phenethyl) cyclopentanol 76

3-(3-(2-cyclopropylethyl)phenyl- propan-1-amine 95

1-(3-(3-amino-1- hydroxypropyl)phenethyl) cyclooctanol 98

1-(3-(3-amino-1- hydroxypropyl)phenethyl) cyclobutanol 100

2-(3-(3-amino-1- hydroxypropyl)phenethyl) cyclohexanol 103

1-(3-(3- aminopropyl)phenethyl) cyclooctanol 105

3-amino-1-(3-(2- cyclooctylethyl)phenyl)propan- 1-ol 115

1-(3-(3-amino-1- hydroxypropyl)phenethyl) cyclopentanol 128

(1S,2S)-3-amino-1-(3-(2-(1- hydroxycyclohexypethyl)phenyl)propane-1,2-diol 129

(1R,2R)-3-amino-1-(3-(2-1- hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diol 130

(1S,2R)-3-amino-1-(3-(2-(1- hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diol 131

(1R,2S)-3-amino-1-(3-(2-(1- hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diol 133

3-(3-(2- cycloheptylethyl)phenyl) propan-1-amine 137

3-amino-1-(3-(2- cycloheptylethyl)phenyl) propan-1-ol 150

1-(3-(3-amino-2- hydroxypropyl)phenethyl) cyclopentanol 151

1-(3-(3-aminopropyl)phenyl)-2- cyclohexylethanone 152

1-(3-(3-amino-2- hydroxypropyl)phenethyl) cyclohexanol 153

2-(3-(3-aminopropyl)phenyl)-1- cyclohexylethanone 154

1-(3-(3-amino-1-hydroxypropyl)-5- fluorophenethyl)cyclohexanol 155

1-(3-(3-amino-1-hydroxypropyl)-2- fluorophenethyl)cyclohexanol 179

(R)-3-(3-amino-1-hydroxypropyl)- N-cyclohexyl-N-methylbenzamide 180

1-(3-((1R,2R)-3-amino-1-hydroxy- 2-methylpropyl)phenethyl) cyclopentanol181

1-(3-(3-aminopropyl)-5- methylphenethyl)cyclohexanol 182

1-(3-(3-aminopropyl)-4- fluorophenethyl)cyclohexanol 183

(E)-1-(3-(3-aminoprop-1- enyl)phenethyl)cyclohexanol 184

1-(3-(3-aminoprop-1- ynyl)phenethyl)cyclohexanol 187

2-(3-(3- aminopropyl)phenethyl) cyclohexanol

In another embodiment, X is —O—, and the compound of Formula (I) can berepresented by a structure of Formula (Ib):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:

-   R₁ and R₂ are each the same or different and independently hydrogen,    C₁-C₅ alkyl, or fluoroalkyl;-   R₃ and R₄ are each the same or different and independently hydrogen    or alkyl;-   R₅ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, or    carbocyclylalkyl;-   R₁₁ and R₁₂ are each the same or different and independently    hydrogen, alkyl, or —C(═O)R₁₃; or-   R₁₁ and R₁₂, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   R₁₃ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl, or    heterocyclyl.

In certain embodiments of the compound having a structure represented byFormula (Ib), each of R₁₁ and R₁₂ is hydrogen.

In other embodiments, R₁₁ is hydrogen and R₁₂ is —C(═O)R₁₃, wherein R₁₃is alkyl.

In other embodiments, each of R₃ and R₄ is hydrogen.

In certain embodiments, R₅ is C₅-C₉ alkyl.

In other certain embodiments, R₅ is carbocyclylalkyl.

In certain other embodiments, R₅ is heteroarylalkyl.

In yet other certain embodiments, R₅ is heterocyclylalkyl.

In further embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₃ and R₄ is hydrogen, and R₅ is C₅-C₉ alkyl. In certain specificembodiments, R₅ is C₅-C₉ alkyl substituted with —OR₆, wherein R₆ ishydrogen or alkyl.

In other embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₃ and R₄ is hydrogen, and R₅ is heteroarylalkyl, wherein the alkyleneportion of R₅ is ethylene, propylene, or butylene.

In other embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₃ and R₄ is hydrogen, and R₅ is heterocyclylalkyl, wherein the alkyleneportion of R₅ is ethylene, propylene, or butylene.

In other embodiments, each of R₁₁ and R₁₂ is hydrogen, each of R₁, R₂,R₃ and R₄ is hydrogen, and R₅ is carbocyclylalkyl, wherein the alkyleneportion of R₅ is ethylene, propylene, or butylene.

Certain compounds disclosed herein have the structures shown in Table 4.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 4 Example Number Structure Name 9

4-(3-(2-aminoethoxy)phenethyl)heptan-4-ol 12

1-(3-(2- aminoethoxy)phenethyl)cyclohexanol 10

1-(3-(2- aminoethoxy)phenethyl)cycloheptanol 11

4-(3-(2-aminoethoxy)phenethyl)tetrahydro- 2H-thiopyran-4-ol 13

6-(3-(2-aminoethoxy)phenyl)hexan-1-ol 14

2-(3-(3- cyclopentylpropyl)phenoxy)ethanamine 36

2-(3-(2-(pyridin-3- yl)ethyl)phenoxy)ethanamine 37

2-(3-(2-(pyridin-2- yl)ethyl)phenoxy)ethanamine 38

2-(3-(2-(thiophen-2- yl)ethyl)phenoxy)ethanamine 50

1-(3-(2-aminoethoxy)phenyl)-3-ethylpentan- 3-ol 51

1-(3-(2-aminoethoxy)phenyl)-3- isopropyl-4-methylpentan-3-ol 52

5-(3-(2-aminoethoxy)phenethyl)nonan-5-ol 53

4-(3-(2-aminoethoxy)phenyl)-2- methylbutan-2-ol 54

1-(3-(2- aminoethoxy)phenethyl)cyclopentanol 64

2-(3-(4-methylpentyl)phenoxy)ethanamine 65

2-(3-(3-phenylpropyl)phenoxy)ethanamine 66

4-(3-(2-aminoethoxy)phenyl)butan-1-ol 67

2-(3-phenethylphenoxy)ethanamine 68

2-(3-(4-phenylbutyl)phenoxy)ethanamine 69

2-(3-(2- methoxyphenethyl)phenoxy)ethanamine 74

2-(3-(2- cyclopropylethyl)phenoxy)ethanamine 75

5-(3-(2-aminoethoxy)phenyl)pentan-1-ol 77

2-(3-hexylphenoxy)ethanamine 78

2-(3-(3-methoxypropyl)phenoxy)ethanamine 81

1-(3-(2-aminoethoxy)phenyl)hexan-3-ol 83

(S)-1-(3-(1-aminopropan-2- yloxy)phenethyl)cyclohexanol 84

1-(3-(2-aminoethoxy)phenyl)-4- methylpentan-3-ol 88

2-(3-(4-methoxybutyl)phenoxy)ethanamine 89

1-(3-(2- aminoethoxy)phenethyl)cyclooctanol 93

5-(3-(2-aminoethoxy)phenyl)-N- methylpentanamide 94

5-(3-(2-aminoethoxy)phenyl)-N,N- dimethylpentanamide 96

5-(3-(2-aminoethoxy)phenyl)pentanamide 99

2-(3-(2- aminoethoxy)phenethyl)cyclohexanol 101

1-(3-(2- aminoethoxy)phenethyl)cyclobutanol 107

2-(3-(5-methoxypentyl)phenoxy)ethanamine 108

2-(3-(2- cyclooctylethyl)phenoxy)ethanamine 114

2-(3-(2-(tetrahydro-2H-pyran-2- yl)ethyl)phenoxy)ethanamine 123

3-(3-(2-aminoethoxy)phenyl)-1- phenylpropan-1-ol 125

3-(3-(2-aminoethoxy)phenyl)propan-1-ol

Certain compounds disclosed herein have the structures shown in Table 5.The example number refers to a specific Example herein that describesthe preparation of the compound having the structure/name shown.

TABLE 5 Example Number Structure Name 127

4-(3-(4-aminobutyl)phenethyl)heptan-4-ol 134

4-(3-(2-aminoethylthio)phenethyl)heptan-4-ol 135

4-(3-(2-aminoethylsulfonyl)phenethyl)heptan-4- ol 136

4-(3-(2-aminoethylamino)phenethyl)heptan-4-ol 139

(S)-4-(3-(2-amino-1- hydroxyethyl)phenethyl)heptan-4-ol 156

3-(3-(cyclohexylthiomethyl)phenyl)prop-2-yn-1- amine 157

3-(3-(cyclohexylsulfonylmethyl)phenyl)prop-2- yn-1-amine 158

3-(3-(cyclohexylthiomethyl)phenyl)propan-1- amine 159

3-(3-(cyclohexylsulfonylmethyl)phenyl)propan- 1-amine 160

(E)-3-(3-(cyclohexyloxymethyl)phenyl)prop-2- en-1-amine 162

4-(3-(2-aminoethyl)phenethyl)heptan-4-ol 163

3-(3-aminopropyl)-o-cyclohexylbenzamide 164

3-(2-aminoethoxy)-N-cyclohexylbenzamide 165

3-(3-aminopropyl)-N-(heptan-4-yl)benzamide 166

3-(3-aminopropyl)-N-(2,6- dimethylphenyl)benzamide 185

4-(3-(3-aminopropoxy)phenethyl)heptan-4-ol 186

4-(3-((2-aminoethoxy)methyl)phenethypheptan- 4-ol

II. DEFINITIONS

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a compound”includes a plurality of such compounds, and reference to “the cell”includes reference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

“Sulfanyl” refers to the —S— radical.

“Sulfinyl” refers to the —S(═O)— radical.

“Sulfonyl” refers to the —S(═O)₂— radical.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Imino” refers to the ═NH radical.

“Thioxo” refers to the ═S radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises five to fifteen carbon atoms (e.g.,C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five to eightcarbon atoms (e.g., C₅-C₅alkyl). The alkyl is attached to the rest ofthe molecule by a single bond, for example, methyl (Me), ethyl (Et),n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylgroup is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to twelve carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to four carbon atoms. Thealkenyl is attached to the rest of the molecule by a single bond, forexample, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwisespecifically in the specification, an alkenyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to twelve carbon atoms. Incertain embodiments, an alkynyl comprises two to eight carbon atoms. Inother embodiments, an alkynyl has two to four carbon atoms. The alkynylis attached to the rest of the molecule by a single bond, for example,ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unlessstated otherwise specifically in the specification, an alkynyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond.

The points of attachment of the alkylene chain to the rest of themolecule and to the radical group can be through one carbon in thealkylene chain or through any two carbons within the chain. Unlessstated otherwise specifically in the specification, an alkylene chain isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo,thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1or 2) where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain. Unless stated otherwise specifically inthe specification, an alkenylene chain is optionally substituted by oneor more of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted unless otherwiseindicated.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from six to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)t-electron system in accordance with the Hückel theory. Aryl groupsinclude, but are not limited to, groups such as phenyl, fluorenyl, andnaphthyl. Unless stated otherwise specifically in the specification, theterm “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroarylor heteroarylalkyl, each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —Re-aryl where R^(c) is analkylene chain as defined above, for example, benzyl, diphenylmethyl andthe like. The alkylene chain part of the aralkyl radical is optionallysubstituted as described above for an alkylene chain. The aryl part ofthe aralkyl radical is optionally substituted as described above for anaryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl is optionally saturated,(i.e., containing single C—C bonds only) or unsaturated (i.e.,containing one or more double bonds or triple bonds.) A fully saturatedcarbocyclyl radical is also referred to as “cycloalkyl.” Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturatedcarbocyclyl is also referred to as “cycloalkenyl.” Examples ofmonocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicalsinclude, for example, adamantyl, norbornyl (i.e.,bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwisestated specifically in the specification, the term “carbocyclyl” ismeant to include carbocyclyl radicals that are optionally substituted byone or more substituents independently selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R^(b)—OR^(a), —R^(b)—SR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(Ra)₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical is optionally substituted as defined above for analkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, andincludes fused or bridged ring systems. The heteroatom(s) in theheterocyclyl radical is optionally oxidized. One or more nitrogen atoms,if present, are optionally quaternized. The heterocyclyl radical ispartially or fully saturated. The heterocyclyl is attached to the restof the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—SR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hickeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—SR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

The compounds, or their pharmaceutically acceptable salts may containone or more asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)-for amino acids. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers (e.g., cis or trans.) Likewise, all possibleisomers, as well as their racemic and optically pure forms, and alltautomeric forms are also intended to be included.

“Stereoisomers” are compounds that have the same sequence of covalentbonds and differ in the relative disposition of their atoms in space.“Enantiomers” refers to two stereoisomers that are nonsuperimposeablemirror images of one another.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas for example, deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N,¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S,³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. All isotopicvariations of the compounds of the present invention, whetherradioactive or not, are encompassed within the scope of the presentinvention.

In certain embodiments, the amine derivative compounds disclosed hereinhave some or all of the ¹H atoms replaced with ²H atoms. The methods ofsynthesis for deuterium-containing amine derivative compounds are knownin the art and include, by way of non-limiting example only, thefollowing synthetic methods.

Deuterated starting materials, such as acid i and acid ii, are readilyavailable and are subjected to the synthetic methods described hereinfor the synthesis of amine derivative compounds.

Other deuterated starting materials are also employed in the synthesisof deuterium-containing amine derivative compounds as shown, in anon-limiting example, in the scheme below. Large numbers ofdeuterium-containing reagents and building blocks are availablecommerically from chemical vendors, such as Aldrich Chemical Co.

Deuterium-transfer reagents, such as lithium aluminum deuteride(LiAlD₄), are employed to transfer deuterium under reducing conditionsto the reaction substrate. The use of LiAlD₄ is illustrated, by way ofexample only, in the reaction schemes below.

Deuterium gas and palladium catalyst are employed to reduce unsaturatedcarbon-carbon linkages and to perform a reductive substitution of arylcarbon-halogen bonds as illustrated, by way of example only, in thereaction schemes below.

In one embodiments, the amine derivative compound contains one deuteriumatom. In another embodiment, the amine derivative compound contains twodeuterium atoms. In another embodiment, the amine derivative compoundcontains three deuterium atoms. In another embodiment, the aminederivative compound contains four deuterium atoms. In anotherembodiment, the amine derivative compound contains five deuterium atoms.In another embodiment, the amine derivative compound contains sixdeuterium atoms. In another embodiment, the amine derivative compound isfully substituted with deuterium atoms and contains no non-exchangeable¹H hydrogen atoms.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the aminederivative compounds described herein is intended to encompass any andall pharmaceutically suitable salt forms. Preferred pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to methods andtechniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

“Non-retinoid compound” refers to any compound that is not a retinoid. Aretinoid is a compound that has a diterpene skeleton possessing atrimethylcyclohexenyl ring and a polyene chain that terminates in apolar end group. Examples of retinoids include retinaldehyde and derivedimine/hydrazide/oxime, retinol and any derived ester, retinyl amine andany derived amide, retinoic acid and any derived ester or amide. Anon-retinoid compound can comprise though not require an internal cyclicgroup (e.g., aromatic group). A non-retinoid compound can contain thoughnot require an amine derivative group.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of an alcohol or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

The compounds of the invention are synthesized by an appropriatecombination of generally well known synthetic methods. Techniques usefulin synthesizing the compounds of the invention are both readily apparentand accessible to those of skill in the relevant art.

The discussion below is offered to illustrate how, in principle, to gainaccess to the compounds claimed under this invention and to give detailson certain of the diverse methods available for use in assembling thecompounds of the invention. However, the discussion is not intended todefine or limit the scope of reactions or reaction sequences that areuseful in preparing the compounds of the present invention. Thecompounds of this invention may be made by the procedures and techniquesdisclosed in the Examples section below, as well as by known organicsynthesis techniques.

III. PREPARATION OF THE AMINE DERIVATIVE COMPOUNDS

In general, the compounds used in the reactions described herein may bemade according to organic synthesis techniques known to those skilled inthis art, starting from commercially available chemicals and/or fromcompounds described in the chemical literature. “Commercially availablechemicals” may be obtained from standard commercial sources includingAcros Organics (Pittsburgh Pa.), Aldrich Chemical (Milwaukee Wis.,including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton ParkUK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada),Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester Pa.), CrescentChemical Co. (Hauppauge N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester N.Y.), Fisher Scientific Co. (Pittsburgh Pa.), FisonsChemicals (Leicestershire UK), Frontier Scientific (Logan Utah), ICNBiomedicals, Inc. (Costa Mesa Calif.), Key Organics (Cornwall U.K.),Lancaster Synthesis (Windham N.H.), Maybridge Chemical Co. Ltd.(Cornwall U.K.), Parish Chemical Co. (Orem Utah), Pfaltz & Bauer, Inc.(Waterbury Conn.), Polyorganix (Houston Tex.), Pierce Chemical Co.(Rockford Ill.), Riedel de Haen AG (Hanover, Germany), Spectrum QualityProduct, Inc. (New Brunswick, N.J.), TCI America (Portland Oreg.), TransWorld Chemicals, Inc. (Rockville Md.), and Wako Chemicals USA, Inc.(Richmond Va.).

Methods known to one of ordinary skill in the art may be identifiedthrough various reference books and databases.

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Quin, L. D. et al. “A Guide to Organophosphorus Chemistry” (2000)Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T. W. G. “OrganicChemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0;Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993)Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals:Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999)John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “OrganicReactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and“Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the amine derivative compounds describedherein is P. H. Stahl & C. G. Wermuth “Handbook of PharmaceuticalSalts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

The term “protecting group” refers to chemical moieties that block someor all reactive moieties of a compound and prevent such moieties fromparticipating in chemical reactions until the protective group isremoved, for example, those moieties listed and described in T. W.Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd ed.John Wiley & Sons (1999). It may be advantageous, where differentprotecting groups are employed, that each (different) protective groupbe removable by a different means. Protective groups that are cleavedunder totally disparate reaction conditions allow differential removalof such protecting groups. For example, protective groups can be removedby acid, base, and hydrogenolysis. Groups such as trityl,dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile andmay be used to protect carboxy and hydroxy reactive moieties in thepresence of amino groups protected with Cbz groups, which are removableby hydrogenolysis, and Fmoc groups, which are base labile. Carboxylicacid moieties may be blocked with base labile groups such as, withoutlimitation, methyl, or ethyl, and hydroxy reactive moieties may beblocked with base labile groups such as acetyl in the presence of aminesblocked with acid labile groups such as tert-butyl carbamate or withcarbamates that are both acid and base stable but hydrolyticallyremovable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups may be blocked with base labile groups such as Fmoc.Carboxylic acid reactive moieties may be blocked withoxidatively-removable protective groups such as 2,4-dimethoxybenzyl,while co-existing amino groups may be blocked with fluoride labile silylcarbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with apalladium(0)-catalyzed reaction in the presence of acid labile t-butylcarbamate or base-labile acetate amine protecting groups. Yet anotherform of protecting group is a resin to which a compound or intermediatemay be attached. As long as the residue is attached to the resin, thatfunctional group is blocked and cannot react. Once released from theresin, the functional group is available to react.

Typical blocking/protecting groups are known in the art and include, butare not limited to the following moieties:

Generally speaking, compounds of Formula (I) can be prepared in astepwise manner involving initial acetylene, or olefin formationfollowed by hydrogenation to provide the alkanyl substituent on thephenyl. The nitrogen-containing moiety can be linked to the phenyl viathe formation and modification of a side chain at the meta-position ofthe alkanyl.

1. Alkanyl Formation

Methods A-C below describe various approaches to alkanyl formation onthe phenyl ring.

More specifically, Method A illustrates the formation of an alkanethrough hydrogenation of an alkyne. Method B shows the construction ofan alkane intermediate through the hydrogenation of a cis or transolefin.

Catalysts suitable for hydrogenation reactions are known to thoseskilled in the art. Exemplary catalysts include, for example, palladiumon charcoal, palladium hydroxide, platinum, platinum oxide, Raneynickel, rhodium, Wilkinson's catalyst (chlorotris(triphenylphosphine)rhodium), and Lindlar's catalyst (Pd—CaCO₃—PbO).

Hydrogen sources suitable for reducing alkynes to alkanes viahydrogenation are known to those skilled in the art. Exemplary hydrogensources include, for example, hydrogen gas, ammonium formate, sodiumborohydride, cyclohexene, cyclohexadiene and hydrazine.

Method B shows the construction of an alkane intermediate through thehydrogenation of a cis or trans olefin.

The alkyne (A-1) and olefin (A-3) can be prepared according to knownmethods in the art (see, e.g., Methods C-G).

Methods C-G illustrate the formation of an alkyne or olefin side chainon a phenyl (indicated by Ar). More specifically, Method C shows thecoupling of a triple bond with a phenyl based on a Sonogashira reaction.Typically, palladium(0) catalyst is used in combination with a base tocouple an aryl halide with an acetylene derivative. R′ can be, forexample, alkyl, aryl, heterocyclyl, heteroaryl, carbocyclyl, orderivatives thereof, which can be further modified, as described herein.

2. Alkanyl Formation

Method D shows the formation of a terminal alkyne. Typically, theSonogashira reaction is used to link an aryl halide to an acetylenederivative such as 2-methyl-3-butyn-2-ol. In a subsequent step, base isused to reveal the terminal alkyne. This alkyne can be further modifiedin subsequent Sonogashira type reactions.

Method E shows the coupling of an olefin with a phenyl based on a Heckreaction. Typically, palladium(0) catalyst is used in combination with abase to couple an aryl halide with a vinyl derivative. R′ can be furthermodified, as described herein.

Method F shows the formation of an olefinic bond based on a Wittigreaction. Typically, a phosphonium salt is coupled to an aldehyde in thepresence of a suitable base during which a molecule of triarylphosphineoxide is eliminated.

Method G shows the formation of an olefinic bond via the elimination ofH₂O in the presence of acid.

In addition, direct alkylation of a phenyl group can be carried out by,for example, coupling an alkyl boronate with a phenyl halide in thepresence of a Pd-based catalyst. Other methods for direct alkylation ofa phenyl ring include, for example, coupling an aralkyl or alkylGrignards reagent with the phenyl ring.

Nitrogen-Containing Side Chain Formation and Modification

Methods H-T below describe various approaches to side chain formationand modifications.

Generally speaking, a suitably substituted phenyl derivative can becoupled to a diverse range of side chains, which may be further modifiedto provide the final linkages and the nitrogen-containing moieties ofcompounds of Formula (I).

Method H illustrates an aryl halide coupled with an allyl alcohol in thepresence of a palladium(0) catalyst. The terminal alcohol group of allylalcohol has been simultaneously oxidized to an aldehyde group, which canbe further modified via reductive amination to an amine (—NR₁R¹ ₂).

Method I illustrates an aldol condensation between an aryl aldehyde oraryl ketone with a nitrile reagent comprising at least one α-hydrogen.The resulting condensation intermediate can be further reduced to anamine (—NR₁₁R₁₂).

Method J shows an acylation reaction to form a ketone-based linkage. Oneskilled in the art will recognize that the R′ group may comprisefunctional groups that can be further modified.

Method K shows a side chain precursor (R′OH) attached to an arylderivative via an oxygen atom in a condensation reaction in which amolecule of H₂O is eliminated. R′ may comprise functional groups thatcan be further modified to prepare linkages and nitrogen-containingmoieties of compounds of Formula (I).

In addition, side chains based on alkyne or olefin deriatives can befirst prepared according to Methods C-G, as previously described. Thealkyne or olefin derivatives can be further hydrogenated and modified toprovide the terminal nitrogen-containing moiety.

The following methods illustrate a variety of synthetic pathways tomanipulate or modify the side chain moiety by reduction, oxidation,nucleophilic or electrophilic substitution, acylation and the like. As aresult, a diverse group of linkages can be synthesized.

Method L illustrates an amination process in which a carboxylic acid isconverted to an amine. Typically, the carboxylic acid (or ester) can befirst reduced to a primary alcohol, which can then be converted to anamine via a mesylate, halide, azide, phthalimide, or Mitsunobu reactionand the like. Suitable reducing agents include, for example, sodiumborohydride (NaBH₄), sodium cyanoborohydride (NaBH₃CN), sodiumtriacetoxyborohydride (NaBH(OCOCH₃)₃), lithium aluminum hydride (LiAIH₄)and the like. As shown, the resulting amine can be furtherfunctionalized, by methods known to those skilled in the art.

An amination process in which a carboxylic acid is first converted to anacid chloride and the halide is displaced by a suitable amine synthon isillustrated in Method M. The resulting amide can be reduced and/orfurther functionalized, by methods known to those skilled in the art.

Additional or alternative modifications can be carried out according tothe methods illustrated below.

Scheme I illustrates a complete synthetic sequence for preparing acompound of Formula (I).

In Scheme I, the side chain moiety is first constructed and the amineprotected. The acetylene moiety is then formed through coupling with aterminal acetylene according to Method C. The coupling product is thendeprotected to give rise to an alkyne. The alkanyl linkage is formedthrough hydrogenation of the alkyne (see, e.g., Method A). Othernitrogen-containing moieties can be further derived from the terminalamine, according to known methods in the art.

In addition to the generic reaction schemes and methods discussed above,other exemplary reaction schemes are also provided to illustrate methodsfor preparing any compound having a structure of Formula (I) or any ofits subgenus structures, including Formulae (Ia) and (Ib).

IV. TREATMENT OF OPHTHALMIC DISEASES AND DISORDERS

Amine derivative compounds as described herein, including compoundshaving the structure as set forth in Formula (I) and substructuresthereof, are useful for treating an ophthalmic disease or disorder byinhibiting one or more steps in the visual cycle.

In an additional embodiment is a non-retinoid compound that inhibits anisomerase reaction resulting in production of 11-cis retinol, whereinsaid isomerase reaction occurs in RPE, and wherein said compound has anED₅₀ value of 1 mg/kg or less when administered to a subject. In afurther embodiment is the non-retinoid compound wherein the ED₅₀ valueis measured after administering a single dose of the compound to saidsubject for about 2 hours or longer. In a further embodiment is thenon-retinoid compound, wherein the non-retinoid compound is an alkoxylcompound. In an additional embodiment is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a non-retinoidcompound as described herein. In an additional embodiment is a methodfor treating an ophthalmic disease or disorder in a subject, comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound asdescribed herein.

In an additional embodiment is a compound that inhibits 11-cis-retinolproduction with an IC₅₀ of about 1 μM or less when assayed in vitro,utilizing extract of cells that express RPE65 and LRAT, wherein theextract further comprises CRALBP, wherein the compound is stable insolution for at least about 1 week at room temperature. In a furtherembodiment, the compound inhibits 11-cis-retinol production with an IC₅₀of about 0.1 μM or less. In a further embodiment, the compound inhibits11-cis-retinol production with an IC₅₀ of about 0.01 μM or less. In afurther embodiment, the compound that inhibits 11-cis-retinol productionis a non-retinoid compound. In an additional embodiment is apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound that inhibits 11-cis-retinol production asdescribed herein. In an additional embodiment is a method for treatingan ophthalmic disease or disorder in a subject, comprising administeringto the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In an additionalembodiment is a method of modulating chromophore flux in a retinoidcycle comprising introducing into a subject a compound that inhibits11-cis-retinol production as described herein.

In an additional embodiment is a method for treating an ophthalmicdisease or disorder in a subject, comprising administering to thesubject a compound of Formula (G) or tautomer, stereoisomer, geometricisomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxideor prodrug thereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from —C(each)₂-C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In an additional embodiment is a method of modulating chromophore fluxin a retinoid cycle comprising introducing into a subject a compound ofFormula (G). In a further embodiment is the method resulting in areduction of lipofuscin pigment accumulated in an eye of the subject. Ina further embodiment is the method resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject, wherein thelipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject. In a furtherembodiment is the method of treating an ophthalmic disease or disorderin a subject as described herein resulting in a reduction of lipofuscinpigment accumulated in an eye of the subject, wherein the lipofuscinpigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein, wherein the ophthalmicdisease or disorder is age-related macular degeneration or Stargardt'smacular dystrophy. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described herein, whereinthe ophthalmic disease or disorder is selected from retinal detachment,hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy,Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinaldisease, diabetic retinopathy, diabetic maculopathy, retinal bloodvessel occlusion, retinopathy of prematurity, or ischemia reperfusionrelated retinal injury, proliferative vitreoretinopathy, retinaldystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy,uveitis, a retinal injury, a retinal disorder associated withAlzheimer's disease, a retinal disorder associated with multiplesclerosis, a retinal disorder associated with Parkinson's disease, aretinal disorder associated with viral infection, a retinal disorderrelated to light overexposure, myopia, and a retinal disorder associatedwith AIDS. In a further embodiment is the method of treating anophthalmic disease or disorder in a subject as described hereinresulting in a reduction of lipofuscin pigment accumulated in an eye ofthe subject.

In a further embodiment is the method of treating an ophthalmic diseaseor disorder in a subject as described herein resulting in a reduction oflipofuscin pigment accumulated in an eye of the subject, wherein thelipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound of Formula (G). In another embodiment is a method of inhibitingdark adaptation of a rod photoreceptor cell of the retina comprisingcontacting the retina with a non-retinoid compound as described herein.In another embodiment is a method of inhibiting dark adaptation of a rodphotoreceptor cell of the retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In another embodiment is a method of inhibiting regeneration ofrhodopsin in a rod photoreceptor cell of the retina comprisingcontacting the retina with a compound of Formula (G). In anotherembodiment is a method of inhibiting regeneration of rhodopsin in a rodphotoreceptor cell of the retina comprising contacting the retina with anon-retinoid compound as described herein. In another embodiment is amethod of inhibiting regeneration of rhodopsin in a rod photoreceptorcell of the retina comprising contacting the retina with a compound thatinhibits 11-cis-retinol production as described herein.

In another embodiment is a method of reducing ischemia in an eye of asubject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of Formula (G).

In an additional embodiment is a method of reducing ischemia in an eyeof a subject comprising administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and anon-retinoid compound as described herein. In an additional embodimentis a method of reducing ischemia in an eye of a subject comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In a further embodimentis the method of reducing ischemia in an eye of a subject, wherein thepharmaceutical composition is administered under conditions and at atime sufficient to inhibit dark adaptation of a rod photoreceptor cell,thereby reducing ischemia in the eye.

In an additional embodiment is a method of inhibiting neovascularizationin the retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a non-retinoid compound as described herein. Inan additional embodiment is a method of inhibiting neovascularization inthe retina of an eye of a subject comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound that inhibits 11-cis-retinolproduction as described herein. In a further embodiment is the method ofinhibiting neovascularization in the retina of an eye of a subject,wherein the pharmaceutical composition is administered under conditionsand at a time sufficient to inhibit dark adaptation of a rodphotoreceptor cell, thereby inhibiting neovascularization in the retina.

In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound of Formula (G). In an additional embodiment is a method ofinhibiting degeneration of a retinal cell in a retina comprisingcontacting the retina with a non-retinoid compound as described herein.In an additional embodiment is a method of inhibiting degeneration of aretinal cell in a retina comprising contacting the retina with acompound that inhibits 11-cis-retinol production as described herein.

In a further embodiment is the method of inhibiting degeneration of aretinal cell in a retina wherein the retinal cell is a retinal neuronalcell. In a further embodiment is the method of inhibiting degenerationof a retinal cell in a retina wherein the retinal neuronal cell is aphotoreceptor cell.

In another embodiment is a method of reducing lipofuscin pigmentaccumulated in a subject's retina comprising administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of Formula (G). In an additionalembodiment is a method of reducing lipofuscin pigment accumulated in asubject's retina wherein the lipofuscin isN-retinylidene-N-retinyl-ethanolamine (A2E).

In an additional embodiment is a method of inhibiting reducinglipofuscin pigment accumulated in a subject's retina comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a non-retinoid compound asdescribed herein. In an additional embodiment is a method of reducinglipofuscin pigment accumulated in a subject's retina comprisingadministering to the subject a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound that inhibits11-cis-retinol production as described herein. In an additionalembodiment is a method of reducing lipofuscin pigment accumulated in asubject's retina wherein the lipofuscin isN-retinylidene-N-retinyl-ethanolamine (A2E).

In an additional embodiment is a method of modulating chromophore fluxin a retinoid cycle comprising introducing into a subject a compound ofFormula (G) or tautomer, stereoisomer, geometric isomer or apharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrugthereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R³⁶ and R³⁷ together    form an oxo; or optionally, R³⁶ and R¹ together form a direct bond    to provide a double bond; or optionally, R³⁶ and R¹ together form a    direct bond, and R³⁷ and R² together form a direct bond to provide a    triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁵ is C₅-C₁₅ alkyl or carbocyclyalkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4.

In a further embodiment is the method for treating an ophthalmic diseaseor disorder in a subject, comprising administering to the subject acompound of Formula (G), wherein the compound of Formula (G) is selectedfrom the group consisting of:

In some embodiments, the compounds disclosed herein function byinhibiting or blocking the activity of a visual cycle trans-cisisomerase. The compounds described herein, may inhibit, block, or insome manner interfere with the isomerization step in the visual cycle.In a particular embodiment, the compound inhibits isomerization of anall-trans-retinyl ester; in certain embodiments, the all-trans-retinylester is a fatty acid ester of all-trans-retinol, and the compoundinhibits isomerization of all-trans-retinol to 11-cis-retinol. Thecompound may bind to, or in some manner interact with, and inhibit theisomerase activity of at least one visual cycle isomerase, which mayalso be referred to herein and in the art as a retinal isomerase or anisomerohydrolase. The compound may block or inhibit binding of anall-trans-retinyl ester substrate to an isomerase. Alternatively, or inaddition, the compound may bind to the catalytic site or region of theisomerase, thereby inhibiting the capability of the enzyme to catalyzeisomerization of an all-trans-retinyl ester substrate. On the basis ofscientific data to date, at least one isomerase that catalyzes theisomerization of all-trans-retinyl esters is believed to be located inthe cytoplasm of RPE cells. As discussed herein, each step, enzyme,substrate, intermediate, and product of the visual cycle is not yetelucidated (see, e.g., Moiseyev et al., Proc. Natl. Acad. Sci. USA102:12413-18 (2004); Chen et al., Invest. Ophthalmol. Vis. Sci.47:1177-84 (2006); Lamb et al. supra).

A method for determining the effect of a compound on isomerase activitymay be performed in vitro as described herein and in the art (Stecher etal., J Biol Chem 274:8577-85 (1999); see also Golczak et al., Proc.Natl. Acad. Sci. USA 102:8162-67 (2005)). Retinal pigment epithelium(RPE) microsome membranes isolated from an animal (such as bovine,porcine, human, for example) may serve as the source of the isomerase.The capability of the amine derivative compounds to inhibit isomerasemay also be determined by an in vivo murine isomerase assay. Briefexposure of the eye to intense light (“photobleaching” of the visualpigment or simply “bleaching”) is known to photo-isomerize almost all11-cis-retinal in the retina. The recovery of 11-cis-retinal afterbleaching can be used to estimate the activity of isomerase in vivo(see, e.g., Maeda et al., J. Neurochem 85:944-956 (2003); Van Hooser etal., J Biol Chem 277:19173-82, 2002). Electroretinographic (ERG)recording may be performed as previously described (Haeseleer et al.,Nat. Neurosci. 7:1079-87 (2004); Sugitomo et al., J. Toxicol. Sci. 22Suppl 2:315-25 (1997); Keating et al., Documenta Ophthalmologica100:77-92 (2000)). See also Deigner et al., Science, 244: 968-971(1989); Gollapalli et al., Biochim Biophys Acta. 1651: 93-101 (2003);Parish, et al., Proc. Natl. Acad. Sci. USA 95:14609-13 (1998); Radu, etal., Proc Natl Acad Sci USA 101: 5928-33 (2004)). In certainembodiments, compounds that are useful for treating a subject who has orwho is at risk of developing any one of the ophthalmic and retinaldiseases or disorders described herein have IC₅₀ levels (compoundconcentration at which 50% of isomerase activity is inhibited) asmeasured in the isomerase assays described herein or known in the artthat is less than about 1 μM; in other embodiments, the determined IC₅₀level is less than about 10 μM; in other embodiments, the determinedIC₅₀ level is less than about 50 μM; in certain other embodiments, thedetermined IC₅₀ level is less than about 100 μM; in other certainembodiments, the determined IC₅₀ level is less than about 10 μM; inother embodiments, the determined IC₅₀ level is less than about 50 μM;in other certain embodiments, the determined IC₅₀ level is less thanabout 100 μM or about 500 μM; in other embodiments, the determined IC₅₀level is between about 1 μM and 10 μM; in other embodiments, thedetermined IC₅₀ level is between about 1 nM and 10 nM. When adminsteredinto a subject, one or more compounds of the present invention exhibitsan ED₅₀ value of about 5 mg/kg, 5 mg/kg or less as ascertained byinhibition of an isomerase reaction that results in production of 11-cisretinol. In some embodiments, the compounds of the present inventionhave ED₅₀ values of about 1 mg/kg when administered into a subject. Inother embodiments, the compounds of the present invention have ED₅₀values of about 0.1 mg/kg when administered into a subject. The ED₅₀values can be measured after about 2 hours, 4 hours, 6 hours, 8 hours orlonger upon administering a subject compound or a pharmaceuticalcomposition thereof.

The compounds described herein may be useful for treating a subject whohas an ophthalmic disease or disorder, particularly a retinal disease ordisorder such as age-related macular degeneration or Stargardt's maculardystrophy.

In one embodiment, the compounds described herein may inhibit (i.e.,prevent, reduce, slow, abrogate, or minimize) accumulation of lipofuscinpigments and lipofuscin-related and/or associated molecules in the eye.In another embodiment, the compounds may inhibit (i.e., prevent, reduce,slow, abrogate, or minimize)N-retinylidene-N-retinylethanolamine (A2E)accumulation in the eye. The ophthalmic disease may result, at least inpart, from lipofuscin pigments accumulation and/or from accumulation ofA2E in the eye. Accordingly, in certain embodiments, methods areprovided for inhibiting or preventing accumulation of lipofuscinpigments and/or A2E in the eye of a subject. These methods compriseadministering to the subject a composition comprising a pharmaceuticallyacceptable or suitable excipient (i.e., pharmaceutically acceptable orsuitable carrier) and an amine derivative compound as described indetail herein, including a compound having the structure as set forth inFormula (I) and substructures thereof, and the specific amine derivativecompounds described herein.

Accumulation of lipofuscin pigments in retinal pigment epithelium (RPE)cells has been linked to progression of retinal diseases that result inblindness, including age-related macular degeneration (De Laey et al.,Retina 15:399-406 (1995)). Lipofuscin granules are autofluorescentlysosomal residual bodies (also called age pigments). The majorfluorescent species of lipofuscin is A2E (an orange-emittingfluorophore), which is a positively charged Schiff-basecondensation-product formed by all-trans retinaldehyde withphosphatidylethanolamine (2:1 ratio) (see, e.g., Eldred et al., Nature361:724-6 (1993); see also, Sparrow, Proc. Natl. Acad. Sci. USA100:4353-54 (2003)). Much of the indigestible lipofuscin pigment isbelieved to originate in photoreceptor cells; deposition in the RPEoccurs because the RPE internalize membranous debris that is discardeddaily by the photoreceptor cells. Formation of this compound is notbelieved to occur by catalysis by any enzyme, but rather A2E forms by aspontaneous cyclization reaction. In addition, A2E has a pyridiniumbisretinoid structure that once formed may not be enzymaticallydegraded. Lipofuscin, and thus A2E, accumulate with aging of the humaneye and also accumulate in a juvenile form of macular degenerationcalled Stargardt's disease, and in several other congenital retinaldystrophies.

A2E may induce damage to the retina via several different mechanisms. Atlow concentrations, A2E inhibits normal proteolysis in lysosomes (Holzet al., Invest. Ophthalmol. Vis. Sci. 40:737-43 (1999)). At higher,sufficient concentrations, A2E may act as a positively chargedlysosomotropic detergent, dissolving cellular membranes, and may alterlysosomal function, release proapoptotic proteins from mitochondria, andultimately kill the RPE cell (see, e.g., Eldred et al., supra; Sparrowet al., Invest. Ophthalmol. Vis. Sci. 40:2988-95 (1999); Holz et al.,supra; Finneman et al., Proc. Natl. Acad. Sci. USA 99:3842-347 (2002);Suter et al., J. Biol. Chem. 275:39625-30 (2000)). A2E is phototoxic andinitiates blue light-induced apoptosis in RPE cells (see, e.g., Sparrowet al., Invest. Ophthalmol. Vis. Sci. 43:1222-27 (2002)). Upon exposureto blue light, photooxidative products of A2E are formed (e.g.,epoxides) that damage cellular macromolecules, including DNA (Sparrow etal., J. Biol. Chem. 278(20):18207-13 (2003)). A2E self-generates singletoxygen that reacts with A2E to generate epoxides at carbon-carbon doublebonds (Sparrow et al., supra). Generation of oxygen reactive speciesupon photoexcitation of A2E causes oxidative damage to the cell, oftenresulting in cell death. An indirect method of blocking formation of A2Eby inhibiting biosynthesis of the direct precursor of A2E,all-trans-retinal, has been described (see U.S. Patent ApplicationPublication No. 2003/0032078). However, the usefulness of the methoddescribed therein is limited because generation of all-trans retinal isan important component of the visual cycle. Other therapies describedinclude neutralizing damage caused by oxidative radical species by usingsuperoxide-dismutase mimetics (see, e.g., U.S. Patent ApplicationPublication No. 2004/0116403) and inhibiting A2E-induced cytochrome Coxidase in retinal cells with negatively charged phospholipids (see,e.g., U.S. Patent Application Publication No. 2003/0050283).

The amine derivative compounds described herein may be useful forpreventing, reducing, inhibiting, or decreasing accumulation (i.e.,deposition) of A2E and A2E-related and/or derived molecules in the RPE.Without wishing to be bound by theory, because the RPE is critical forthe maintenance of the integrity of photoreceptor cells, preventing,reducing, or inhibiting damage to the RPE may inhibit degeneration(i.e., enhance the survival or increase or prolong cell viability) ofretinal neuronal cells, particularly, photoreceptor cells. Compoundsthat bind specifically to or interact with A2E A2E-related and/orderived molecules or that affect A2E formation or accumulation may alsoreduce, inhibit, prevent, or decrease one or more toxic effects of A2Eor of A2E-related and/or derived molecules that result in retinalneuronal cell (including a photoreceptor cell) damage, loss, orneurodegeneration, or in some manner decrease retinal neuronal cellviability. Such toxic effects include induction of apoptosis,self-generation of singlet oxygen and generation of oxygen reactivespecies; self-generation of singlet oxygen to form A2E-epoxides thatinduce DNA lesions, thus damaging cellular DNA and inducing cellulardamage; dissolving cellular membranes; altering lysosomal function; andeffecting release of proapoptotic proteins from mitochondria.

In other embodiments, the compounds described herein may be used fortreating other ophthalmic diseases or disorders, for example, glaucoma,cone-rod dystrophy, retinal detachment, hemorrhagic or hypertensiveretinopathy, retinitis pigmentosa, optic neuropathy, inflammatoryretinal disease, proliferative vitreoretinopathy, genetic retinaldystrophies, traumatic injury to the optic nerve (such as by physicalinjury, excessive light exposure, or laser light), hereditary opticneuropathy, neuropathy due to a toxic agent or caused by adverse drugreactions or vitamin deficiency, Sorsby's fundus dystrophy, uveitis, aretinal disorder associated with Alzheimer's disease, a retinal disorderassociated with multiple sclerosis; a retinal disorder associated withviral infection (cytomegalovirus or herpes simplex virus), a retinaldisorder associated with Parkinson's disease, a retinal disorderassociated with AIDS, or other forms of progressive retinal atrophy ordegeneration. In another specific embodiment, the disease or disorderresults from mechanical injury, chemical or drug-induced injury, thermalinjury, radiation injury, light injury, laser injury. The subjectcompounds are useful for treating both hereditary and non-hereditaryretinal dystrophy. These methods are also useful for preventingophthalmic injury from environmental factors such as light-inducedoxidative retinal damage, laser-induced retinal damage, “flash bombinjury,” or “light dazzle”, refractive errors including but not limitedto myopia (see, e.g., Quinn G E et al. Nature 1999; 399:113-114; ZadnikK et al. Nature 2000; 404:143-144; Gwiazda J et al. Nature 2000; 404:144), etc.

In other embodiments, methods are provided herein for inhibitingneovascularization (including but not limited to neovascular glycoma) inthe retina using any one or more of the amine derivative compound asdescribed in detail herein, including a compound having the structure asset forth in Formula (I) and substructures thereof, and the specificamine derivative compounds described herein. In certain otherembodiments, methods are provided for reducing hypoxia in the retinausing the compounds described herein. These methods compriseadministering to a subject, in need thereof, a composition comprising apharmaceutically acceptable or suitable excipient (i.e.,pharmaceutically acceptable or suitable carrier) and an amine derivativecompound as described in detail herein, including a compound having thestructure as set forth in Formula (I) and substructures thereof, and thespecific amine derivative compounds described herein.

Merely by way of explanation and without being bound by any theory, andas discussed in further detail herein, dark-adapted rod photoreceptorsengender a very high metabolic demand (i.e., expenditure of energy (ATPconsumption) and consumption of oxygen). The resultant hypoxia may causeand/or exacerbate retinal degeneration, which is likely exaggeratedunder conditions in which the retinal vasculature is alreadycompromised, including, but not limited to, such conditions as diabeticretinopathy, macular edema, diabetic maculopathy, retinal blood vesselocclusion (which includes retinal venous occlusion and retinal arterialocclusion), retinopathy of prematurity, ischemia reperfusion relatedretinal injury, as well as in the wet form of age-related maculardegeneration (AMD). Furthermore, retinal degeneration and hypoxia maylead to neovascularization, which in turn may worsen the extent ofretinal degeneration. The amine derivative compounds described hereinthat modulate the visual cycle can be administered to prevent, inhibit,and/or delay dark adaptation of rod photoreceptor cells, and maytherefore reduce metabolic demand, thereby reducing hypoxia andinhibiting neovascularization.

By way of background, oxygen is a critical molecule for preservation ofretinal function in mammals, and retinal hypoxia may be a factor in manyretinal diseases and disorders that have ischemia as a component. Inmost mammals (including humans) with dual vascular supply to the retina,oxygenation of the inner retina is achieved through the intraretinalmicrovasculature, which is sparse compared to the choriocapillaris thatsupplies oxygen to the RPE and photoreceptors. The different vascularsupply networks create an uneven oxygen tension across the thickness ofthe retina (Cringle et al., Invest. Ophthalmol. Vis. Sci. 43:1922-27(2002)). Oxygen fluctuation across the retinal layers is related to boththe differing capillary densities and disparity in oxygen consumption byvarious retinal neurons and glia.

Local oxygen tension can significantly affect the retina and itsmicrovasculature by regulation of an array of vasoactive agents,including, for example, vascular endothelial growth factor (VEGF). (See,e.g., Werdich et al., Exp. Eye Res. 79:623 (2004); Arden et al., Br. J.Ophthalmol. 89:764 (2005)). Rod photoreceptors are believed to have thehighest metabolic rate of any cell in the body (see, e.g., Arden et al.,supra). During dark adaptation, the rod photoreceptors recover theirhigh cytoplasmic calcium levels via cGMP-gated calcium channels withconcomitant extrusion of sodium ions and water. The efflux of sodiumfrom the cell is an ATP-dependent process, such that the retinal neuronsconsume up to an estimated five times more oxygen under scotopic (i.e.,dark adapted), compared with photopic (i.e., light adapted) conditions.Thus, during characteristic dark adaptation of photoreceptors, the highmetabolic demand leads to significant local reduction of oxygen levelsin the dark-adapted retina (Ahmed et al, Invest. Ophthalmol. Vis. Sci.34:516 (1993)).

Without being bound by any one theory, retinal hypoxia may be furtherincreased in the retina of subjects who have diseases or conditions suchas, for example, central retinal vein occlusion in which the retinalvasculature is already compromised. Increasing hypoxia may increasesusceptibility to sight-threatening, retinal neovascularization.Neovascularization is the formation of new, functional microvascularnetworks with red blood cell perfusion, and is a characteristic ofretinal degenerative disorders, including, but not limited to, diabeticretinopathy, retinopathy of prematurity, wet AMD and central retinalvein occlusions. Preventing or inhibiting dark adaptation of rodphotoreceptor cells, thereby decreasing expenditure of energy andconsumption of oxygen (i.e., reducing metabolic demand), may inhibit orslow retinal degeneration, and/or may promote regeneration of retinalcells, including rod photoreceptor cells and retinal pigment epithelial(RPE) cells, and may reduce hypoxia and may inhibit neovascularization.

Methods are described herein for inhibiting (i.e., reducing, preventing,slowing or retarding, in a biologically or statistically significantmanner) degeneration of retinal cells (including retinal neuronal cellsas described herein and RPE cells) and/or for reducing (i.e., preventingor slowing, inhibiting, abrogating in a biologically or statisticallysignificant manner) retinal ischemia. Methods are also provided forinhibiting (i.e., reducing, preventing, slowing or retarding, in abiologically or statistically significant manner) neovascularization inthe eye, particularly in the retina. Such methods comprise contactingthe retina, and thus, contacting retinal cells (including retinalneuronal cells such as rod photoreceptor cells, and RPE cells) with atleast one of the amine derivative compounds described herein thatinhibits at least one visual cycle trans-cis isomerase (which mayinclude inhibition of isomerization of an all-trans-retinyl ester),under conditions and at a time that may prevent, inhibit, or delay darkadaptation of a rod photoreceptor cell in the retina. As described infurther detail herein, in particular embodiments, the compound thatcontacts the retina interacts with an isomerase enzyme or enzymaticcomplex in a RPE cell in the retina and inhibits, blocks, or in somemanner interferes with the catalytic activity of the isomerase. Thus,isomerization of an all-trans-retinyl ester is inhibited or reduced. Theamine derivative compounds described herein or compositions comprisingsaid compounds may be administered to a subject who has developed andmanifested an ophthalmic disease or disorder or who is at risk ofdeveloping an ophthalmic disease or disorder, or to a subject whopresents or who is at risk of presenting a condition such as retinalneovascularization or retinal ischemia.

By way of background, the visual cycle (also called retinoid cycle)refers to the series of enzyme and light-mediated conversions betweenthe 11-cis and all-trans forms of retinol/retinal that occur in thephotoreceptor and retinal pigment epithelial (RPE) cells of the eye. Invertebrate photoreceptor cells, a photon causes isomerization of the11-cis-retinylidene chromophore to all-trans-retinylidene coupled to thevisual opsin receptors. This photoisomerization triggers conformationalchanges of opsins, which, in turn, initiate the biochemical chain ofreactions termed phototransduction (Filipek et al., Annu. Rev. Physiol.65 851-79 (2003)). After absorption of light and photoisomerization of11-cis-retinal to all-trans retinal, regeneration of the visualchromophore is a critical step in restoring photoreceptors to theirdark-adapted state. Regeneration of the visual pigment requires that thechromophore be converted back to the 11-cis-configuration (reviewed inMcBee et al., Prog. Retin. Eye Res. 20:469-52 (2001)). The chromophoreis released from the opsin and reduced in the photoreceptor by retinoldehydrogenases. The product, all-trans-retinol, is trapped in theadjacent retinal pigment epithelium (RPE) in the form of insoluble fattyacid esters in subcellular structures known as retinosomes (Imanishi etal., J. Cell Biol. 164:373-78 (2004)).

During the visual cycle in rod receptor cells, the 11-cis retinalchromophore within the visual pigment molecule, which is calledrhodopsin, absorbs a photon of light and is isomerized to the all-transconfiguration, thereby activating the phototransduction cascade.Rhodopsin is a G-protein coupled receptor (GPCR) that consists of sevenmembrane-spanning helices that are interconnected by extracellular andcytoplasmic loops. When the all-trans form of the retinoid is stillcovalently bound to the pigment molecule, the pigment is referred to asmetarhodopsin, which exists in different forms (e.g., metarhodopsin Iand metarhodopsin II). The all-trans retinoid is then hydrolyzed and thevisual pigment is in the form of the apoprotein, opsin, which is alsocalled apo-rhodopsin in the art and herein. This all-trans retinoid istransported or chaperoned out of the photoreceptor cell and across theextracellular space to the RPE cells, where the retinoid is converted tothe 11-cis isomer. The movement of the retinoids between the RPE andphotoreceptors cells is believed to be accomplished by differentchaperone polypeptides in each of the cell types. See Lamb et al.,Progress in Retinal and Eye Research 23:307-80 (2004).

Under light conditions, rhodopsin continually transitions through thethree forms, rhodopsin, metarhodopsin, and apo-rhodopsin. When most ofthe visual pigment is in the rhodopsin form (i.e., bound with 11-cisretinal), the rod photoreceptor cell is in a “dark-adapted” state. Whenthe visual pigment is predominantly in the metarhodopsin form (i.e.,bound with all-trans-retinal), the state of the photoreceptor cell isreferred to as a “light-adapted,” and when the visual pigment isapo-rhodopsin (or opsin) and no longer has bound chromophore, the stateof the photoreceptor cell is referred to as “rhodopsin-depleted.” Eachof the three states of the photoreceptor cell has different energyrequirements, and differing levels of ATP and oxygen are consumed. Inthe dark-adapted state, rhodopsin has no regulatory effect on cationchannels, which are open, resulting in an influx of cations (Na⁺/K⁺ andCa²⁺). To maintain the proper level of these cations in the cell duringthe dark state, the photoreceptor cells actively transport the cationsout of the cell via ATP-dependent pumps. Thus maintenance of this “darkcurrent” requires a large amount of energy, resulting in high metabolicdemand. In the light-adapted state, metarhodopsin triggers an enzymaticcascade process that results in hydrolysis of GMP, which in turn, closescation-specific channels in the photoreceptor cell membrane. In therhodopsin-depleted state, the chromophore is hydrolyzed frommetarhodopsin to form the apoprotein, opsin (apo-rhodopsin), whichpartially regulates the cation channels such that the rod photoreceptorcells exhibit an attenuated current compared with the photoreceptor inthe dark-adapted state, resulting in a moderate metabolic demand.

Under normal light conditions, the incidence of rod photoreceptors inthe dark adapted state is small, in general, 2% or less, and the cellsare primarily in the light-adapted or rhodopsin-depleted states, whichoverall results in a relatively low metabolic demand compared with cellsin the dark-adapted state. At night, however, the relative incidence ofthe dark-adapted photoreceptor state increases profoundly, due to theabsence of light adaptation and to the continued operation of the “dark”visual cycle in RPE cells, which replenishes the rod photoreceptor cellswith 11-cis-retinal. This shift to dark adaptation of the rodphotoreceptor causes an increase in metabolic demand (that is, increasedATP and oxygen consumption), leading ultimately to retinal hypoxia andsubsequent initiation of angiogenesis. Most ischaemic insults to theretina therefore occur in the dark, for example, at night during sleep.

Without being bound by any theory, therapeutic intervention during the“dark” visual cycle may prevent retinal hypoxia and neovascularizationthat are caused by high metabolic activity in the dark-adapted rodphotoreceptor cell. Merely by way of one example, altering the “dark”visual cycle by administering any one of the compounds described herein,which is an isomerase inhibitor, rhodopsin (i.e., 11-cis retinal bound)may be reduced or depleted, preventing or inhibiting dark adaptation ofrod photoreceptors. This in turn may reduce retinal metabolic demand,attenuating the nighttime risk of retinal ischemia andneovascularization, and thereby inhibiting or slowing retinaldegeneration.

In one embodiment, at least one of the compounds described herein (i.e.,a compound having the structure as set forth in Formula (I) andsubstructures thereof described herein) that, for example, blocks,reduces, inhibits, or in some manner attenuates the catalytic activityof a visual cycle isomerase in a statistically or biologicallysignificant manner, may prevent, inhibit, or delay dark adaptation of arod photoreceptor cell, thereby inhibiting (i.e., reducing, abrogating,preventing, slowing the progression of, or decreasing in a statisticallyor biologically significant manner) degeneration of retinal cells (orenhancing survival of retinal cells) of the retina of an eye. In anotherembodiment, the amine derivative compounds may prevent or inhibit darkadaptation of a rod photoreceptor cell, thereby reducing ischemia (i.e.,decreasing, preventing, inhibiting, slowing the progression of ischemiain a statistically or biologically significant manner). In yet anotherembodiment, any one of the amine derivative compounds described hereinmay prevent dark adaptation of a rod photoreceptor cell, therebyinhibiting neovascularization in the retina of an eye. Accordingly,methods are provided herein for inhibiting retinal cell degeneration,for inhibiting neovascularization in the retina of an eye of a subject,and for reducing ischemia in an eye of a subject wherein the methodscomprise administering at least one amine derivative compound describedherein, under conditions and at a time sufficient to prevent, inhibit,or delay dark adaptation of a rod photoreceptor cell. These methods andcompositions are therefore useful for treating an ophthalmic disease ordisorder including, but not limited to, diabetic retinopathy, diabeticmaculopathy, retinal blood vessel occlusion, retinopathy of prematurity,or ischemia reperfusion related retinal injury.

The amine derivative compounds described herein (i.e., an aminederivative compound as described in detail herein, including a compoundhaving the structure as set forth in Formula (I), and substructuresthereof, and the specific amine derivative compounds described herein)may prevent (i.e., delay, slow, inhibit, or decrease) recovery of thevisual pigment chromophore, which may prevent or inhibit or retard theformation of retinals and may increase the level of retinyl esters,which perturbs the visual cycle, inhibiting regeneration of rhodopsin,and which prevents, slows, delays or inhibits dark adaptation of a rodphotoreceptor cell. In certain embodiments, when dark adaptation of rodphotoreceptor cells is prevented in the presence of the compound, darkadaptation is substantially prevented, and the number or percent of rodphotoreceptor cells that are rhodopsin-depleted or light adapted isincreased compared with the number or percent of cells that arerhodopsin-depleted or light-adapted in the absence of the agent. Thus,in certain embodiments when dark adaptation of rod photoreceptor cellsis prevented (i.e., substantially prevented), only at least 2% of rodphotoreceptor cells are dark-adapted, similar to the percent or numberof cells that are in a dark-adapted state during normal, lightconditions. In other embodiments, at least 5-10%, 10-20%, 20-30%,30-40%, 40-50%, 50-60%, or 60-70% of rod photoreceptor cells aredark-adapted after administration of an agent. In other embodiments, thecompound acts to delay dark adaptation, and in the presence of thecompound dark adaptation of rod photoreceptor cells may be delayed 30minutes, one hour, two hours, three hours, or four hours compared todark adaptation of rod photoreceptors in the absence of the compound. Bycontrast, when an amine derivative compound is administered such thatthe compound effectively inhibits isomerization of substrate duringlight-adapted conditions, the compound is administered in such a mannerto minimize the percent of rod photoreceptor cells that aredark-adapted, for example, only 2%, 5%, 10%, 20%, or 25% of rodphotoreceptors are dark-adapted (see e.g., U.S. Patent ApplicationPublication No. 2006/0069078; Patent Application No. PCT/US2007/002330).

In the retina in the presence of at least one amine derivative compound,regeneration of rhodopsin in a rod photoreceptor cell may be inhibitedor the rate of regeneration may be reduced (i.e., inhibited, reduced, ordecreased in a statistically or biologically significant manner), atleast in part, by preventing the formation of retinals, reducing thelevel of retinals, and/or increasing the level of retinyl esters. Todetermine the level of regeneration of rhodopsin in a rod photoreceptorcell, the level of regeneration of rhodopsin (which may be called afirst level) may be determined prior to permitting contact between thecompound and the retina (i.e., prior to administration of the agent).After a time sufficient for the compound and the retina and cells of theretina to interact, (i.e., after administration of the compound), thelevel of regeneration of rhodopsin (which may be called a second level)may be determined. A decrease in the second level compared with thefirst level indicates that the compound inhibits regeneration ofrhodopsin. The level of rhodopsin generation may be determined aftereach dose, or after any number of doses, and ongoing throughout thetherapeutic regimen to characterize the effect of the agent onregeneration of rhodopsin.

In certain embodiments, the subject in need of the treatments describedherein, may have a disease or disorder that results in or causesimpairment of the capability of rod photoreceptors to regeneraterhodopsin in the retina. By way of example, inhibition of rhodopsinregeneration (or reduction of the rate of rhodopsin regeneration) may besymptomatic in patients with diabetes. In addition to determining thelevel of regeneration of rhodopsin in the subject who has diabetesbefore and after administration of an amine derivative compounddescribed herein, the effect of the compound may also be characterizedby comparing inhibition of rhodopsin regeneration in a first subject (ora first group or plurality of subjects) to whom the compound isadministered, to a second subject (or second group or plurality ofsubjects) who has diabetes but who does not receive the agent.

In another embodiment, a method is provided for preventing or inhibitingdark adaptation of a rod photoreceptor cell (or a plurality of rodphotoreceptor cells) in a retina comprising contacting the retina and atleast one of the amine derivative compounds described herein (i.e., acompound as described in detail herein, including a compound having thestructure as set forth in Formula (I), and substructures thereof, andthe specific amine derivative compounds described herein), underconditions and at a time sufficient to permit interaction between theagent and an isomerase present in a retinal cell (such as an RPE cell).A first level of 11-cis-retinal in a rod photoreceptor cell in thepresence of the compound may be determined and compared to a secondlevel of 11-cis-retinal in a rod photoreceptor cell in the absence ofthe compound. Prevention or inhibition of dark adaptation of the rodphotoreceptor cell is indicated when the first level of 11-cis-retinalis less than the second level of 11-cis-retinal.

Inhibiting regeneration of rhodopsin may also include increasing thelevel of 11-cis-retinyl esters present in the RPE cell in the presenceof the compound compared with the level of 11-cis-retinyl esters presentin the RPE cell in the absence of the compound (i.e., prior toadministration of the agent). A two-photon imaging technique may be usedto view and analyze retinosome structures in the RPE, which structuresare believed to store retinyl esters (see, e.g., Imanishi et al., J.Cell Biol. 164:373-83 (2004), Epub 2004 January 26.). A first level ofretinyl esters may be determined prior to administration of thecompound, and a second level of retinyl esters may be determined afteradministration of a first dose or any subsequent dose, wherein anincrease in the second level compared to the first level indicates thatthe compound inhibits regeneration of rhodopsin.

Retinyl esters may be analyzed by gradient HPLC according to methodspracticed in the art (see, for example, Mata et al., Neuron 36:69-80(2002); Trevino et al. J. Exp. Biol. 208:4151-57 (2005)). To measure11-cis and all-trans retinals, retinoids may be extracted by aformaldehyde method (see, e.g., Suzuki et al., Vis. Res. 28:1061-70(1988); Okajima and Pepperberg, Exp. Eye Res. 65:331-40 (1997)) or by ahydroxylamine method (see, e.g., Groenendijk et al., Biochim. Biophys.Acta. 617:430-38 (1980)) before being analyzed on isocratic HPLC (see,e.g., Trevino et al., supra). The retinoids may be monitoredspectrophotometrically (see, e.g., Maeda et al., J. Neurochem.85:944-956 (2003); Van Hooser et al., J. Biol. Chem. 277:19173-82(2002)).

In another embodiment of the methods described herein for treating anophthalmic disease or disorder, for inhibiting retinal cell degeneration(or enhancing retinal cell survival), for inhibiting neovascularization,and for reducing ischemia in the retina, preventing or inhibiting darkadaptation of a rod photoreceptor cell in the retina comprisesincreasing the level of apo-rhodopsin (also called opsin) in thephotoreceptor cell. The total level of the visual pigment approximatesthe sum of rhodopsin and apo-rhodopsin and the total level remainsconstant. Therefore, preventing, delaying, or inhibiting dark adaptationof the rod photoreceptor cell may alter the ratio of apo-rhodopsin torhodopsin. In particular embodiments, preventing, delaying, orinhibiting dark adaptation by administering an amine derivative compounddescribed herein may increase the ratio of the level of apo-rhodopsin tothe level of rhodopsin compared to the ratio in the absence of the agent(for example, prior to administration of the agent). An increase in theratio (i.e., a statistically or biologically significant increase) ofapo-rhodopsin to rhodopsin indicates that the percent or number of rodphotoreceptor cells that are rhodopsin-depleted is increased and thatthe percent or number of rod photoreceptor cells that are dark-adaptedis decreased. The ratio of apo-rhodopsin to rhodopsin may be determinedthroughout the course of therapy to monitor the effect of the agent.

Determining or characterizing the capability of compound to prevent,delay, or inhibit dark adaptation of a rod photoreceptor cell may bedetermined in animal model studies. The level of rhodopsin and the ratioof apo-rhodopsin to rhodopsin may be determined prior to administration(which may be called a first level or first ratio, respectively) of theagent and then after administration of a first or any subsequent dose ofthe agent (which may be called a second level or second ratio,respectively) to determine and to demonstrate that the level ofapo-rhodopsin is greater than the level of apo-rhodopsin in the retinaof animals that did not receive the agent. The level of rhodopsin in rodphotoreceptor cells may be performed according to methods practiced inthe art and provided herein (see, e.g., Yan et al. J. Biol. Chem.279:48189-96 (2004)).

A subject in need of such treatment may be a human or may be a non-humanprimate or other animal (i.e., veterinary use) who has developedsymptoms of an ophthalmic disease or disorder or who is at risk fordeveloping an ophthalmic disease or disorder. Examples of non-humanprimates and other animals include but are not limited to farm animals,pets, and zoo animals (e.g., horses, cows, buffalo, llamas, goats,rabbits, cats, dogs, chimpanzees, orangutans, gorillas, monkeys,elephants, bears, large cats, etc.).

Also provided herein are methods for inhibiting (reducing, slowing,preventing) degeneration and enhancing retinal neuronal cell survival(or prolonging cell viability) comprising administering to a subject acomposition comprising a pharmaceutically acceptable carrier and anamine derivative compound described in detail herein, including acompound having any one of the structures set forth in Formula (I) andsubstructures thereof, and specific amine derivative compounds recitedherein. Retinal neuronal cells include photoreceptor cells, bipolarcells, horizontal cells, ganglion cells, and amacrine cells. In anotherembodiment, methods are provided for enhancing survival or inhibitingdegeneration of a mature retinal cell such as a RPE cell or a Miillerglial cell. In other embodiments, a method for preventing or inhibitingphotoreceptor degeneration in an eye of a subject are provided. A methodthat prevents or inhibits photoreceptor degeneration may include amethod for restoring photoreceptor function in an eye of a subject. Suchmethods comprise administering to the subject a composition comprisingan amine derivative compound as described herein and a pharmaceuticallyor acceptable carrier (i.e., excipient or vehicle). More specifically,these methods comprise administering to a subject a pharmaceuticallyacceptable excipient and an amine derivative compound described herein,including a compound having any one of the structures set forth inFormula (I) or substructures thereof described herein. Without wishingto be bound by theory, the compounds described herein may inhibit anisomerization step of the retinoid cycle (i.e., visual cycle) and/or mayslow chromophore flux in a retinoid cycle in the eye.

The ophthalmic disease may result, at least in part, from lipofuscinpigment(s) accumulation and/or from accumulation ofN-retinylidene-N-retinylethanolamine (A2E) in the eye. Accordingly, incertain embodiments, methods are provided for inhibiting or preventingaccumulation of lipofuscin pigment(s) and/or A2E in the eye of asubject. These methods comprise administering to the subject acomposition comprising a pharmaceutically acceptable carrier and anamine derivative compound as described in detail herein, including acompound having the structure as set forth in Formula (I) orsubstructures thereof.

An amine derivative compound can be administered to a subject who has anexcess of a retinoid in an eye (e.g., an excess of 11-cis-retinol or11-cis-retinal), an excess of retinoid waste products or intermediatesin the recycling of all-trans-retinal, or the like. Methods describedherein and practiced in the art may be used to determine whether thelevel of one or more endogenous retinoids in a subject are altered(increased or decreased in a statistically significant or biologicallysignificant manner) during or after administration of any one of thecompounds described herein.

Rhodopsin, which is composed of the protein opsin and retinal (a vitaminA form), is located in the membrane of the photoreceptor cell in theretina of the eye and catalyzes the only light-sensitive step in vision.The 11-cis-retinal chromophore lies in a pocket of the protein and isisomerized to all-trans retinal when light is absorbed. Theisomerization of retinal leads to a change of the shape of rhodopsin,which triggers a cascade of reactions that lead to a nerve impulse thatis transmitted to the brain by the optic nerve.

Methods of determining endogenous retinoid levels in a vertebrate eye,and an excess or deficiency of such retinoids, are disclosed in, forexample, U.S. Patent Application Publication No: 2005/0159662 (thedisclosure of which is incorporated by reference herein in itsentirety). Other methods of determining endogenous retinoid levels in asubject, which is useful for determining whether levels of suchretinoids are above the normal range, and include for example, analysisby high pressure liquid chromatography (HPLC) of retinoids in abiological sample from a subject. For example, retinoid levels can bedetermined in a biological sample that is a blood sample (which includesserum or plasma) from a subject. A biological sample may also includevitreous fluid, aqueous humor, intraocular fluid, subretinal fluid, ortears.

For example, a blood sample can be obtained from a subject, anddifferent retinoid compounds and levels of one or more of the retinoidcompounds in the sample can be separated and analyzed by normal phasehigh pressure liquid chromatography (HPLC) (e.g., with a HP1100 HPLC anda Beckman, Ultrasphere-Si, 4.6 mm×250 mm column using 10% ethylacetate/90% hexane at a flow rate of 1.4 ml/minute). The retinoids canbe detected by, for example, detection at 325 nm using a diode-arraydetector and HP Chemstation A.03.03 software. An excess in retinoids canbe determined, for example, by comparison of the profile of retinoids(i.e., qualitative, e.g., identity of specific compounds, andquantitative, e.g., the level of each specific compound) in the samplewith a sample from a normal subject. Persons skilled in the art who arefamiliar with such assays and techniques and will readily understandthat appropriate controls are included.

As used herein, increased or excessive levels of endogenous retinoid,such as 11-cis-retinol or 11-cis-retinal, refer to levels of endogenousretinoid higher than those found in a healthy eye of a young vertebrateof the same species.

Administration of an amine derivative compound can reduce or eliminatethe requirement for endogenous retinoid.

In certain embodiments, the level of endogenous retinoid may be comparedbefore and after any one or more doses of an amine derivative compoundis administered to a subject to determine the effect of the compound onthe level of endogenous retinoids in the subject.

In another embodiment, the methods described herein for treating anophthalmic disease or disorder, for inhibiting neovascularization, andfor reducing ischemia in the retina comprise administering at least oneof the amine derivative compounds described herein, thereby effecting adecrease in metabolic demand, which includes effecting a reduction inATP consumption and in oxygen consumption in rod photoreceptor cells. Asdescribed herein, consumption of ATP and oxygen in a dark-adapted rodphotoreceptor cell is greater than in rod photoreceptor cells that arelight-adapted or rhodopsin-depleted; thus, use of the compounds in themethods described herein may reduce the consumption of ATP in the rodphotoreceptor cells that are prevented, inhibited, or delayed from darkadaptation compared with rod photoreceptor cells that are dark-adapted(such as the cells prior to administration or contact with the compoundor cells that are never exposed to the compound).

The methods described herein that may prevent or inhibit dark adaptationof a rod photoreceptor cell may therefore reduce hypoxia (i.e., reducein a statistically or biologically significant manner) in the retina.For example, the level of hypoxia (a first level) may be determinedprior to initiation of the treatment regimen, that is, prior to thefirst dosing of the compound (or a composition, as described herein,comprising the compound). The level of hypoxia (for example, a secondlevel) may be determined after the first dosing, and/or after any secondor subsequent dosing to monitor and characterize hypoxia throughout thetreatment regimen. A decrease (reduction) in the second (or anysubsequent) level of hypoxia compared to the level of hypoxia prior toinitial administration indicates that the compound and the treatmentregiment prevent dark adaptation of the rod photoreceptor cells and maybe used for treating ophthalmic diseases and disorders. Consumption ofoxygen, oxygenation of the retina, and/or hypoxia in the retina may bedetermined using methods practiced in the art. For example, oxygenationof the retina may be determined by measuring the fluorescence offlavoproteins in the retina (see, e.g., U.S. Pat. No. 4,569,354).

Another exemplary method is retinal oximetry that measures blood oxygensaturation in the large vessels of the retina near the optic disc. Suchmethods may be used to identify and determine the extent of retinalhypoxia before changes in retinal vessel architecture can be detected.

A biological sample may be a blood sample (from which serum or plasmamay be prepared), biopsy specimen, body fluids (e.g., vitreous fluid,aqueous humor, intraocular fluid, subretinal fluid, or tears), tissueexplant, organ culture, or any other tissue or cell preparation from asubject or a biological source. A sample may further refer to a tissueor cell preparation in which the morphological integrity or physicalstate has been disrupted, for example, by dissection, dissociation,solubilization, fractionation, homogenization, biochemical or chemicalextraction, pulverization, lyophilization, sonication, or any othermeans for processing a sample derived from a subject or biologicalsource. The subject or biological source may be a human or non-humananimal, a primary cell culture (e.g., a retinal cell culture), orculture adapted cell line, including but not limited to, geneticallyengineered cell lines that may contain chromosomally integrated orepisomal recombinant nucleic acid sequences, immortalized orimmortalizable cell lines, somatic cell hybrid cell lines,differentiated or differentiatable cell lines, transformed cell lines,and the like. Mature retinal cells, including retinal neuronal cells,RPE cells, and Müller glial cells, may be present in or isolated from abiological sample as described herein. For example, the mature retinalcell may be obtained from a primary or long-term cell culture or may bepresent in or isolated from a biological sample obtained from a subject(human or non-human animal).

3. Retinal Cells

The retina is a thin layer of nervous tissue located between thevitreous body and choroid in the eye. Major landmarks in the retina arethe fovea, the macula, and the optic disc. The retina is thickest nearthe posterior sections and becomes thinner near the periphery. Themacula is located in the posterior retina and contains the fovea andfoveola. The foveola contains the area of maximal cone density and,thus, imparts the highest visual acuity in the retina. The foveola iscontained within the fovea, which is contained within the macula.

The peripheral portion of the retina increases the field of vision. Theperipheral retina extends anterior to the ciliary body and is dividedinto four regions: the near periphery (most posterior), themid-periphery, the far periphery, and the ora serrata (most anterior).The ora serrata denotes the termination of the retina.

The term neuron (or nerve cell) as understood in the art and used hereindenotes a cell that arises from neuroepithelial cell precursors. Matureneurons (i.e. fully differentiated cells) display several specificantigenic markers. Neurons may be classified functionally into fourgroups: (1) afferent neurons (or sensory neurons) that transmitinformation into the brain for conscious perception and motorcoordination; (2) motor neurons that transmit commands to muscles andglands; (3) interneurons that are responsible for local circuitry; and(4) projection interneurons that relay information from one region ofthe brain to another region and therefore have long axons. Interneuronsprocess information within specific subregions of the brain and haverelatively shorter axons. A neuron typically has four defined regions:the cell body (or soma); an axon; dendrites; and presynaptic terminals.The dendrites serve as the primary input of information from otherneural cells. The axon carries the electrical signals that are initiatedin the cell body to other neurons or to effector organs. At thepresynaptic terminals, the neuron transmits information to another cell(the postsynaptic cell), which may be another neuron, a muscle cell, ora secretory cell.

The retina is composed of several types of neuronal cells. As describedherein, the types of retinal neuronal cells that may be cultured invitro by this method include photoreceptor cells, ganglion cells, andinterneurons such as bipolar cells, horizontal cells, and amacrinecells. Photoreceptors are specialized light-reactive neural cells andcomprise two major classes, rods and cones. Rods are involved inscotopic or dim light vision, whereas photopic or bright light visionoriginates in the cones. Many neurodegenerative diseases, such as AMD,that result in blindness affect photoreceptors.

Extending from their cell bodies, the photoreceptors have twomorphologically distinct regions, the inner and outer segments. Theouter segment lies furthermost from the photoreceptor cell body andcontains disks that convert incoming light energy into electricalimpulses (phototransduction). The outer segment is attached to the innersegment with a very small and fragile cilium. The size and shape of theouter segments vary between rods and cones and are dependent uponposition within the retina. See Hogan, “Retina” in Histology of theHuman Eye: an Atlas and Text Book (Hogan et al. (eds). W B Saunders;Philadelphia, Pa. (1971)); Eye and Orbit, 8^(th) Ed., Bron et al.,(Chapman and Hall, 1997).

Ganglion cells are output neurons that convey information from theretinal interneurons (including horizontal cells, bipolar cells,amacrine cells) to the brain. Bipolar cells are named according to theirmorphology, and receive input from the photoreceptors, connect withamacrine cells, and send output radially to the ganglion cells. Amacrinecells have processes parallel to the plane of the retina and havetypically inhibitory output to ganglion cells. Amacrine cells are oftensubclassified by neurotransmitter or neuromodulator or peptide (such ascalretinin or calbindin) and interact with each other, with bipolarcells, and with photoreceptors. Bipolar cells are retinal interneuronsthat are named according to their morphology; bipolar cells receiveinput from the photoreceptors and sent the input to the ganglion cells.Horizontal cells modulate and transform visual information from largenumbers of photoreceptors and have horizontal integration (whereasbipolar cells relay information radially through the retina).

Other retinal cells that may be present in the retinal cell culturesdescribed herein include glial cells, such as Müller glial cells, andretinal pigment epithelial cells (RPE). Glial cells surround nerve cellbodies and axons. The glial cells do not carry electrical impulses butcontribute to maintenance of normal brain function. Müller glia, thepredominant type of glial cell within the retina, provide structuralsupport of the retina and are involved in the metabolism of the retina(e.g., contribute to regulation of ionic concentrations, degradation ofneurotransmitters, and remove certain metabolites (see, e.g., Kljavin etal., J. Neurosci. 11:2985 (1991))). Müller's fibers (also known assustentacular fibers of retina) are sustentacular neuroglial cells ofthe retina that run through the thickness of the retina from theinternal limiting membrane to the bases of the rods and cones where theyform a row of junctional complexes.

Retinal pigment epithelial (RPE) cells form the outermost layer of theretina, separated from the blood vessel-enriched choroids by Bruch'smembrane. RPE cells are a type of phagocytic epithelial cell, with somefunctions that are macrophage-like, which lies immediately below theretinal photoreceptors. The dorsal surface of the RPE cell is closelyapposed to the ends of the rods, and as discs are shed from the rodouter segment they are internalized and digested by RPE cells. Similarprocess occurs with the disc of the cones. RPE cells also produce,store, and transport a variety of factors that contribute to the normalfunction and survival of photoreceptors. Another function of RPE cellsis to recycle vitamin A as it moves between photoreceptors and the RPEduring light and dark adaptation in the process known as the visualcycle.

Described herein is an exemplary long-term in vitro cell culture systempermits and promotes the survival in culture of mature retinal cells,including retinal neurons, for at least 2-4 weeks, over 2 months, or foras long as 6 months. The cell culture system may be used for identifyingand characterizing the amine derivative compounds that are useful in themethods described herein for treating and/or preventing an ophthalmicdisease or disorder or for preventing or inhibiting accumulation in theeye of lipofuscin(s) and/or A2E. Retinal cells are isolated fromnon-embryonic, non-tumorigenic tissue and have not been immortalized byany method such as, for example, transformation or infection with anoncogenic virus. The cell culture system comprises all the major retinalneuronal cell types (photoreceptors, bipolar cells, horizontal cells,amacrine cells, and ganglion cells), and also may include other matureretinal cells such as retinal pigment epithelial cells and Müller glialcells.

For example, a blood sample can be obtained from a subject, anddifferent retinoid compounds and levels of one or more of the retinoidcompounds in the sample can be separated and analyzed by normal phasehigh pressure liquid chromatography (HPLC) (e.g., with a HP1100 HPLC anda Beckman, Ultrasphere-Si, 4.6 mm×250 mm column using 10% ethylacetate/90% hexane at a flow rate of 1.4 ml/minute). The retinoids canbe detected by, for example, detection at 325 nm using a diode-arraydetector and HP Chemstation A.03.03 software. An excess in retinoids canbe determined, for example, by comparison of the profile of retinoids(i.e., qualitative, e.g., identity of specific compounds, andquantitative, e.g., the level of each specific compound) in the samplewith a sample from a normal subject. Persons skilled in the art who arefamiliar with such assays and techniques and will readily understandthat appropriate controls are included.

As used herein, increased or excessive levels of endogenous retinoid,such as 11-cis-retinol or 11-cis-retinal, refer to levels of endogenousretinoid higher than those found in a healthy eye of a young vertebrateof the same species. Administration of an amine derivative compound andreduce or eliminate the requirement for endogenous retinoid.

4. In Vivo and In Vitro Methods for Determining TherapeuticEffectiveness of Compounds

In one embodiment, methods are provided for using the compoundsdescribed herein for enhancing or prolonging retinal cell survival,including retinal neuronal cell survival and RPE cell survival. Alsoprovided herein are methods for inhibiting or preventing degeneration ofa retinal cell, including a retinal neuronal cell (e.g., a photoreceptorcell, an amacrine cell, a horizontal cell, a bipolar cell, and aganglion cell) and other mature retinal cells such as retinal pigmentepithelial cells and Müller glial cells using the compounds describedherein. Such methods comprise, in certain embodiments, administration ofan amine derivative compound as described herein. Such a compound isuseful for enhancing retinal cell survival, including photoreceptor cellsurvival and retinal pigment epithelia survival, inhibiting or slowingdegeneration of a retinal cell, and thus increasing retinal cellviability, which can result in slowing or halting the progression of anophthalmic disease or disorder or retinal injury, which are describedherein.

The effect of an amine derivative compound on retinal cell survival(and/or retinal cell degeneration) may be determined by using cellculture models, animal models, and other methods that are describedherein and practiced by persons skilled in the art. By way of example,and not limitation, such methods and assays include those described inOglivie et al., Exp. Neurol. 161:675-856 (2000); U.S. Pat. No.6,406,840; WO 01/81551; WO 98/12303; U.S. Patent Application No.2002/0009713; WO 00/40699; U.S. Pat. No. 6,117,675; U.S. Pat. No.5,736,516; WO 99/29279; WO 01/83714; WO 01/42784; U.S. Pat. No.6,183,735; U.S. Pat. No. 6,090,624; WO 01/09327; U.S. Pat. No.5,641,750; U.S. Patent Application Publication No. 2004/0147019; andU.S. Patent Application Publication No. 2005/0059148.

Compounds described herein that may be useful for treating an ophthalmicdisease or disorder (including a retinal disease or disorder) mayinhibit, block, impair, or in some manner interfere with one or moresteps in the visual cycle (also called the retinoid cycle herein and inthe art). Without wishing to be bound by a particular theory, an aminederivative compound may inhibit or block an isomerization step in thevisual cycle, for example, by inhibiting or blocking a functionalactivity of a visual cycle trans-cis isomerase. The compounds describedherein may inhibit, directly or indirectly, isomerization ofall-trans-retinol to 11-cis-retinol. The compounds may bind to, or insome manner interact with, and inhibit the isomerase activity of atleast one isomerase in a retinal cell. Any one of the compoundsdescribed herein may also directly or indirectly inhibit or reduce theactivity of an isomerase that is involved in the visual cycle. Thecompound may block or inhibit the capability of the isomerase to bind toone or more substrates, including but not limited to, anall-trans-retinyl ester substrate or all-trans-retinol. Alternatively,or in addition, the compound may bind to the catalytic site or region ofthe isomerase, thereby inhibiting the capability of the enzyme tocatalyze isomerization of at least one substrate. On the basis ofscientific data to date, an at least one isomerase that catalyzes theisomerization of a substrate during the visual cycle is believed to belocated in the cytoplasm of RPE cells. As discussed herein, each step,enzyme, substrate, intermediate, and product of the visual cycle is notyet elucidated. While a polypeptide called RPE65, which has been foundin the cytoplasm and membrane bound in RPE cells, is hypothesized tohave isomerase activity (and has also been referred to in the art ashaving isomerohydrolase activity) (see, e.g., Moiseyev et al., Proc.Natl. Acad. Sci. USA 102:12413-18 (2004); Chen et al., Invest.Ophthalmol. Vis. Sci. 47:1177-84 (2006)), other persons skilled in theart believe that the RPE65 acts primarily as a chaperone forall-trans-retinyl esters (see, e.g., Lamb et al. supra).

Exemplary methods are described herein and practiced by persons skilledin the art for determining the level of enzymatic activity of a visualcycle isomerase in the presence of any one of the compounds describedherein. A compound that decreases isomerase activity may be useful fortreating an ophthalmic disease or disorder. Thus, methods are providedherein for detecting inhibition of isomerase activity comprisingcontacting (i.e., mixing, combining, or in some manner permitting thecompound and isomerase to interact) a biological sample comprising theisomerase and an amine derivative compound described herein and thendetermining the level of enzymatic activity of the isomerase. A personhaving skill in the art will appreciate that as a control, the level ofactivity of the isomerase in the absence of a compound or in thepresence of a compound known not to alter the enzymatic activity of theisomerase can be determined and compared to the level of activity in thepresence of the compound. A decrease in the level of isomerase activityin the presence of the compound compared to the level of isomeraseactivity in the absence of the compound indicates that the compound maybe useful for treating an ophthalmic disease or disorder, such asage-related macular degeneration or Stargardt's disease. A decrease inthe level of isomerase activity in the presence of the compound comparedto the level of isomerase activity in the absence of the compoundindicates that the compound may also be useful in the methods describedherein for inhibiting or preventing dark adaptation, inhibitingneovascularization and reducing hypoxia and thus useful for treating anophthalmic disease or disorder, for example, diabetic retinopathy,diabetic maculopathy, retinal blood vessel occlusion, retinopathy ofprematurity, or ischemia reperfusion related retinal injury.

The capability of an amine derivative compound described herein toinhibit or to prevent dark adaptation of a rod photoreceptor cell byinhibiting regeneration of rhodopsin may be determined by in vitroassays and/or in vivo animal models. By way of example, inhibition ofregeneration may be determined in a mouse model in which a diabetes-likecondition is induced chemically or in a diabetic mouse model (see, e.g.,Phipps et al., Invest. Ophthalmol. Vis. Sci. 47:3187-94 (2006); Ramseyet al., Invest. Ophthalmol. Vis. Sci. 47:5116-24 (2006)). The level ofrhodopsin (a first level) may be determined (for example,spectrophotometrically) in the retina of animals prior to administrationof the agent and compared with the level (a second level) of rhodopsinmeasured in the retina of animals after administration of the agent. Adecrease in the second level of rhodopsin compared with the first levelof rhodopsin indicates that the agent inhibits regeneration ofrhodopsin. The appropriate controls and study design to determinewhether regeneration of rhodopsin is inhibited in a statisticallysignificant or biologically significant manner can be readily determinedand implemented by persons skilled in the art.

Methods and techniques for determining or characterizing the effect ofany one of the compounds described herein on dark adaptation andrhodopsin regeneration in rod photoreceptor cells in a mammal, includinga human, may be performed according to procedures described herein andpracticed in the art. For example, detection of a visual stimulus afterexposure to light (i.e., photobleaching) versus time in darkness may bedetermined before administration of the first dose of the compound andat a time after the first dose and/or any subsequent dose. A secondmethod for determining prevention or inhibition of dark adaptation bythe rod photoreceptor cells includes measurement of the amplitude of atleast one, at least two, at least three, or more electroretinogramcomponents, which include, for example, the a-wave and the b-wave. See,for example, Lamb et al., supra; Asi et al., Documenta Ophthalmologica79:125-39 (1992).

Inhibiting regeneration of rhodopsin by an amine derivative compounddescribed herein comprises reducing the level of the chromophore,11-cis-retinal, that is produced and present in the RPE cell, andconsequently reducing the level of 11-cis-retinal that is present in thephotoreceptor cell. Thus, the compound, when permitted to contact theretina under suitable conditions and at a time sufficient to preventdark adaptation of a rod photoreceptor cell and to inhibit regenerationof rhodopsin in the rod photoreceptor cell, effects a reduction in thelevel of 11-cis-retinal in a rod photoreceptor cell (i.e., astatistically significant or biologically significant reduction). Thatis, the level of 11-cis retinal in a rod photoreceptor cell is greaterprior to administration of the compound when compared with the level of11-cis-retinal in the photoreceptor cell after the first and/or anysubsequent administration of the compound.

A first level of 11-cis-retinal may be determined prior toadministration of the compound, and a second level of 11-cis-retinal maybe determined after administration of a first dose or any subsequentdose to monitor the effect of the compound. A decrease in the secondlevel compared to the first level indicates that the compound inhibitsregeneration of rhodopsin and thus inhibits or prevents dark adaptationof the rod photoreceptor cells.

An exemplary method for determining or characterizing the capability ofan amine derivative compound to reduce retinal hypoxia includesmeasuring the level of retinal oxygenation, for example, by MagneticResonance Imaging (MRI) to measure changes in oxygen pressure (see,e.g., Luan et al., Invest. Ophthalmol. Vis. Sci. 47:320-28 (2006)).Methods are also available and routinely practiced in the art todetermine or characterize the capability of compounds described hereinto inhibit degeneration of a retinal cell (see, e.g., Wenzel et al.,Prog. Retin. Eye Res. 24:275-306 (2005)).

Animal models may be used to characterize and identify compounds thatmay be used to treat retinal diseases and disorders. A recentlydeveloped animal model may be useful for evaluating treatments formacular degeneration has been described by Ambati et al. (Nat. Med.9:1390-97 (2003); Epub 2003 Oct. 19). This animal model is one of only afew exemplary animal models presently available for evaluating acompound or any molecule for use in treating (including preventing)progression or development of a retinal disease or disorder. Animalmodels in which the ABCR gene, which encodes an ATP-binding cassettetransporter located in the rims of photoreceptor outer segment discs,may be used to evaluate the effect of a compound. Mutations in the ABCRgene are associated with Stargardt's disease, and heterozygous mutationsin ABCR have been associated with AMD. Accordingly, animals have beengenerated with partial or total loss of ABCR function and may used tocharacterize the amine derivative compounds described herein. (See,e.g., Mata et al., Invest. Ophthalmol. Sci. 42:1685-90 (2001); Weng etal., Cell 98:13-23 (1999); Mata et al., Proc. Natl. Acad. Sci. USA97:7154-49 (2000); US 2003/0032078; U.S. Pat. No. 6,713,300). Otheranimal models include the use of mutant ELOVL4 transgenic mice todetermine lipofuscin accumulation, electrophysiology, and photoreceptordegeneration, or prevention or inhibition thereof (see, e.g., Karan etal., Proc. Natl. Acad. Sci. USA 102:4164-69 (2005)).

The effect of any one of the compounds described herein may bedetermined in a diabetic retinopathy animal model, such as described inLuan et al. or may be determined in a normal animal model, in which theanimals have been light or dark adapted in the presence and absence ofany one of the compounds described herein. Another exemplary method fordetermining the capability of the agent to reduce retinal hypoxiameasures retinal hypoxia by deposition of a hydroxyprobe (see, e.g., deGooyer et al. (Invest. Ophthalmol. Vis. Sci. 47:5553-60 (2006)). Such atechnique may be performed in an animal model using Rho⁻/Rho⁻ knockoutmice (see de Gooyer et al., supra) in which at least one compounddescribed herein is administered to group(s) of animals in the presenceand absence of the at least one compound, or may be performed in normal,wildtype animals in which at least one compound described herein isadministered to group(s) of animals in the presence and absence of theat least one compound. Other animal models include models fordetermining photoreceptor function, such as rat models that measureelctroretinographic (ERG) oscillatory potentials (see, e.g., Liu et al.,Invest. Ophthalmol. Vis. Sci. 47:5447-52 (2006); Akula et al., Invest.Ophthalmol. Vis. Sci. 48:4351-59 (2007); Liu et al., Invest. Ophthalmol.Vis. Sci. 47:2639-47 (2006); Dembinska et al., Invest. Ophthalmol. Vis.Sci. 43:2481-90 (2002); Penn et al., Invest. Ophthalmol. Vis. Sci.35:3429-35 (1994); Hancock et al., Invest. Ophthalmol. Vis. Sci.45:1002-1008 (2004)).

A method for determining the effect of a compound on isomerase activitymay be performed in vitro as described herein and in the art (Stecher etal., J. Biol. Chem. 274:8577-85 (1999); see also Golczak et al., Proc.Natl. Acad. Sci. USA 102:8162-67 (2005)). Retinal pigment epithelium(RPE) microsome membranes isolated from an animal (such as bovine,porcine, human, for example) may serve as the source of the isomerase.The capability of the amine derivative compounds to inhibit isomerasemay also be determined by an in vivo murine isomerase assay. Briefexposure of the eye to intense light (“photobleaching” of the visualpigment or simply “bleaching”) is known to photo-isomerize almost all11-cis-retinal in the retina. The recovery of 11-cis-retinal afterbleaching can be used to estimate the activity of isomerase in vivo(see, e.g., Maeda et al., J. Neurochem. 85:944-956 (2003); Van Hooser etal., J. Biol. Chem. 277:19173-82, 2002). Electroretinographic (ERG)recording may be performed as previously described (Haeseleer et al.,Nat. Neurosci. 7:1079-87 (2004); Sugitomo et al., J. Toxicol. Sci. 22Suppl 2:315-25 (1997); Keating et al., Documenta Ophthalmologica100:77-92 (2000)). See also Deigner et al., Science, 244: 968-971(1989); Gollapalli et al., Biochim. Biophys. Acta 1651: 93-101 (2003);Parish, et al., Proc. Natl. Acad. Sci. USA 95:14609-13 (1998); Radu etal., Proc Natl Acad Sci USA 101: 5928-33 (2004).

Cell culture methods, such as the method described herein, are alsouseful for determining the effect of a compound described herein onretinal neuronal cell survival. Exemplary cell culture models aredescribed herein and described in detail in U.S. Patent ApplicationPublication No. US 2005-0059148 and U.S. Patent Application PublicationNo. US2004-0147019 (which are incorporated by reference in theirentirety), which are useful for determining the capability of an aminederivative compound as described herein to enhance or prolong survivalof neuronal cells, particularly retinal neuronal cells, and of retinalpigment epithelial cells, and inhibit, prevent, slow, or retarddegeneration of an eye, or the retina or retinal cells thereof, or theRPE, and which compounds are useful for treating ophthalmic diseases anddisorders.

The cell culture model comprises a long-term or extended culture ofmature retinal cells, including retinal neuronal cells (e.g.,photoreceptor cells, amacrine cells, ganglion cells, horizontal cells,and bipolar cells). The cell culture system and methods for producingthe cell culture system provide extended culture of photoreceptor cells.The cell culture system may also comprise retinal pigment epithelial(RPE) cells and Miiller glial cells.

The retinal cell culture system may also comprise a cell stressor. Theapplication or the presence of the stressor affects the mature retinalcells, including the retinal neuronal cells, in vitro, in a manner thatis useful for studying disease pathology that is observed in a retinaldisease or disorder. The cell culture model provides an in vitroneuronal cell culture system that will be useful in the identificationand biological testing of an amine derivative compound that is suitablefor treatment of neurological diseases or disorders in general, and fortreatment of degenerative diseases of the eye and brain in particular.The ability to maintain primary, in vitro-cultured cells from matureretinal tissue, including retinal neurons over an extended period oftime in the presence of a stressor enables examination of cell-to-cellinteractions, selection and analysis of neuroactive compounds andmaterials, use of a controlled cell culture system for in vitro CNS andophthalmic tests, and analysis of the effects on single cells from aconsistent retinal cell population.

The cell culture system and the retinal cell stress model comprisecultured mature retinal cells, retinal neurons, and a retinal cellstressor, which may be used for screening and characterizing an aminederivative compound that are capable of inducing or stimulating theregeneration of CNS tissue that has been damaged by disease. The cellculture system provides a mature retinal cell culture that is a mixtureof mature retinal neuronal cells and non-neuronal retinal cells. Thecell culture system comprises all the major retinal neuronal cell types(photoreceptors, bipolar cells, horizontal cells, amacrine cells, andganglion cells), and may also include other mature retinal cells such asRPE and Miiller glial cells. By incorporating these different types ofcells into the in vitro culture system, the system essentially resemblesan “artificial organ” that is more akin to the natural in vivo state ofthe retina. Viability of one or more of the mature retinal cell typesthat are isolated (harvested) from retinal tissue and plated for tissueculture may be maintained for an extended period of time, for example,from two weeks up to six months. Viability of the retinal cells may bedetermined according to methods described herein and known in the art.Retinal neuronal cells, similar to neuronal cells in general, are notactively dividing cells in vivo and thus cell division of retinalneuronal cells would not necessarily be indicative of viability. Anadvantage of the cell culture system is the ability to culture amacrinecells, photoreceptors, and associated ganglion projection neurons andother mature retinal cells for extended periods of time, therebyproviding an opportunity to determine the effectiveness of an aminederivative compound described herein for treatment of retinal disease.

The biological source of the retinal cells or retinal tissue may bemammalian (e.g., human, non-human primate, ungulate, rodent, canine,porcine, bovine, or other mammalian source), avian, or from othergenera. Retinal cells including retinal neurons from post-natalnon-human primates, post-natal pigs, or post-natal chickens may be used,but any adult or post-natal retinal tissue may be suitable for use inthis retinal cell culture system.

In certain instances, the cell culture system may provide for robustlong-term survival of retinal cells without inclusion of cells derivedfrom or isolated or purified from non-retinal tissue. Such a cellculture system comprises cells isolated solely from the retina of theeye and thus is substantially free of types of cells from other parts orregions of the eye that are separate from the retina, such as theciliary body, iris, choroid, and vitreous. Other cell culture methodsinclude the addition of non-retinal cells, such as ciliary body celland/or stem cells (which may or may not be retinal stem cells) and/oradditional purified glial cells.

The in vitro retinal cell culture systems described herein may serve asphysiological retinal models that can be used to characterize aspects ofthe physiology of the retina. This physiological retinal model may alsobe used as a broader general neurobiology model. A cell stressor may beincluded in the model cell culture system. A cell stressor, which asdescribed herein is a retinal cell stressor, adversely affects theviability or reduces the viability of one or more of the differentretinal cell types, including types of retinal neuronal cells, in thecell culture system. A person skilled in the art would readilyappreciate and understand that as described herein a retinal cell thatexhibits reduced viability means that the length of time that a retinalcell survives in the cell culture system is reduced or decreased(decreased lifespan) and/or that the retinal cell exhibits a decrease,inhibition, or adverse effect of a biological or biochemical function(e.g., decreased or abnormal metabolism; initiation of apoptosis; etc.)compared with a retinal cell cultured in an appropriate control cellsystem (e.g., the cell culture system described herein in the absence ofthe cell stressor). Reduced viability of a retinal cell may be indicatedby cell death; an alteration or change in cell structure or morphology;induction and/or progression of apoptosis; initiation, enhancement,and/or acceleration of retinal neuronal cell neurodegeneration (orneuronal cell injury).

Methods and techniques for determining cell viability are described indetail herein and are those with which skilled artisans are familiar.These methods and techniques for determining cell viability may be usedfor monitoring the health and status of retinal cells in the cellculture system and for determining the capability of the aminederivative compounds described herein to alter (preferably increase,prolong, enhance, improve) retinal cell or retinal pigment epithelialcell viability or retinal cell survival.

The addition of a cell stressor to the cell culture system is useful fordetermining the capability of an amine derivative compound to abrogate,inhibit, eliminate, or lessen the effect of the stressor. The retinalcell culture system may include a cell stressor that is chemical (e.g.,A2E, cigarette smoke concentrate); biological (for example, toxinexposure; beta-amyloid; lipopolysaccharides); or non-chemical, such as aphysical stressor, environmental stressor, or a mechanical force (e.g.,increased pressure or light exposure) (see, e.g., US 2005-0059148).

The retinal cell stressor model system may also include a cell stressorsuch as, but not limited to, a stressor that may be a risk factor in adisease or disorder or that may contribute to the development orprogression of a disease or disorder, including but not limited to,light of varying wavelengths and intensities; A2E; cigarette smokecondensate exposure; oxidative stress (e.g., stress related to thepresence of or exposure to hydrogen peroxide, nitroprusside, Zn++, orFe++); increased pressure (e.g., atmospheric pressure or hydrostaticpressure), glutamate or glutamate agonist (e.g., N-methyl-D-aspartate(NMDA); alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA);kainic acid; quisqualic acid; ibotenic acid; quinolinic acid; aspartate;trans-1-aminocyclopentyl-1,3-dicarboxylate (ACPD)); amino acids (e.g.,aspartate, L-cysteine; beta-N-methylamine-L-alanine); heavy metals (suchas lead); various toxins (for example, mitochondrial toxins (e.g.,malonate, 3-nitroproprionic acid; rotenone, cyanide); MPTP(1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine), which metabolizes toits active, toxic metabolite MPP+(1-methyl-4-phenylpryidine));6-hydroxydopamine; alpha-synuclein; protein kinase C activators (e.g.,phorbol myristate acetate); biogenic amino stimulants (for example,methamphetamine, MDMA (3-4 methylenedioxymethamphetamine)); or acombination of one or more stressors. Useful retinal cell stressorsinclude those that mimic a neurodegenerative disease that affects anyone or more of the mature retinal cells described herein. A chronicdisease model is of particular importance because most neurodegenerativediseases are chronic. Through use of this in vitro cell culture system,the earliest events in long-term disease development processes may beidentified because an extended period of time is available for cellularanalysis.

A retinal cell stressor may alter (i.e., increase or decrease in astatistically significant manner) viability of retinal cells such as byaltering survival of retinal cells, including retinal neuronal cells andRPE cells, or by altering neurodegeneration of retinal neuronal cellsand/or RPE cells. Preferably, a retinal cell stressor adversely affectsa retinal neuronal cell or RPE cell such that survival of a retinalneuronal cell or RPE cell is decreased or adversely affected (i.e., thelength of time during which the cells are viable is decreased in thepresence of the stressor) or neurodegeneration (or neuron cell injury)of the cell is increased or enhanced. The stressor may affect only asingle retinal cell type in the retinal cell culture or the stressor mayaffect two, three, four, or more of the different cell types. Forexample, a stressor may alter viability and survival of photoreceptorcells but not affect all the other major cell types (e.g., ganglioncells, amacrine cells, horizontal cells, bipolar cells, RPE, and Miillerglia). Stressors may shorten the survival time of a retinal cell (invivo or in vitro), increase the rapidity or extent of neurodegenerationof a retinal cell, or in some other manner adversely affect theviability, morphology, maturity, or lifespan of the retinal cell.

The effect of a cell stressor (in the presence and absence of an aminederivative compound) on the viability of retinal cells in the cellculture system may be determined for one or more of the differentretinal cell types. Determination of cell viability may includeevaluating structure and/or a function of a retinal cell continually atintervals over a length of time or at a particular time point after theretinal cell culture is prepared. Viability or long term survival of oneor more different retinal cell types or one or more different retinalneuronal cell types may be examined according to one or more biochemicalor biological parameters that are indicative of reduced viability, suchas apoptosis or a decrease in a metabolic function, prior to observationof a morphological or structural alteration.

A chemical, biological, or physical cell stressor may reduce viabilityof one or more of the retinal cell types present in the cell culturesystem when the stressor is added to the cell culture under conditionsdescribed herein for maintaining the long-term cell culture.Alternatively, one or more culture conditions may be adjusted so thatthe effect of the stressor on the retinal cells can be more readilyobserved. For example, the concentration or percent of fetal bovineserum may be reduced or eliminated from the cell culture when cells areexposed to a particular cell stressor (see, e.g., US 2005-0059148).Alternatively, retinal cells cultured in media containing serum at aparticular concentration for maintenance of the cells may be abruptlyexposed to media that does not contain any level of serum.

The retinal cell culture may be exposed to a cell stressor for a periodof time that is determined to reduce the viability of one or moreretinal cell types in the retinal cell culture system. The cells may beexposed to a cell stressor immediately upon plating of the retinal cellsafter isolation from retinal tissue. Alternatively, the retinal cellculture may be exposed to a stressor after the culture is established,or any time thereafter. When two or more cell stressors are included inthe retinal cell culture system, each stressor may be added to the cellculture system concurrently and for the same length of time or may beadded separately at different time points for the same length of time orfor differing lengths of time during the culturing of the retinal cellsystem. An amine derivative compound may be added before the retinalcell culture is exposed to a cell stressor, may be added concurrentlywith the cell stressor, or may be added after exposure of the retinalcell culture to the stressor.

Photoreceptors may be identified using antibodies that specifically bindto photoreceptor-specific proteins such as opsins, peripherins, and thelike. Photoreceptors in cell culture may also be identified as amorphologic subset of immunocytochemically labeled cells by using apan-neuronal marker or may be identified morphologically in enhancedcontrast images of live cultures. Outer segments can be detectedmorphologically as attachments to photoreceptors.

Retinal cells including photoreceptors can also be detected byfunctional analysis. For example, electrophysiology methods andtechniques may be used for measuring the response of photoreceptors tolight. Photoreceptors exhibit specific kinetics in a graded response tolight. Calcium-sensitive dyes may also be used to detect gradedresponses to light within cultures containing active photoreceptors. Foranalyzing stress-inducing compounds or potential neurotherapeutics,retinal cell cultures can be processed for immunocytochemistry, andphotoreceptors and/or other retinal cells can be counted manually or bycomputer software using photomicroscopy and imaging techniques.

Other immunoassays known in the art (e.g., ELISA, immunoblotting, flowcytometry) may also be useful for identifying and characterizing theretinal cells and retinal neuronal cells of the cell culture modelsystem described herein.

The retinal cell culture stress models may also be useful foridentification of both direct and indirect pharmacologic agent effectsby the bioactive agent of interest, such as an amine derivative compoundas described herein. For example, a bioactive agent added to the cellculture system in the presence of one or more retinal cell stressors maystimulate one cell type in a manner that enhances or decreases thesurvival of other cell types. Cell/cell interactions andcell/extracellular component interactions may be important inunderstanding mechanisms of disease and drug function. For example, oneneuronal cell type may secrete trophic factors that affect growth orsurvival of another neuronal cell type (see, e.g., WO 99/29279).

In another embodiment, an amine derivative compound is incorporated intoscreening assays comprising the retinal cell culture stress model systemdescribed herein to determine whether and/or to what level or degree thecompound increases or prolongs viability (i.e., increases in astatistically significant or biologically significant manner) of aplurality of retinal cells. A person skilled in the art would readilyappreciate and understand that as described herein a retinal cell thatexhibits increased viability means that the length of time that aretinal cell survives in the cell culture system is increased (increasedlifespan) and/or that the retinal cell maintains a biological orbiochemical function (normal metabolism and organelle function; lack ofapoptosis; etc.) compared with a retinal cell cultured in an appropriatecontrol cell system (e.g., the cell culture system described herein inthe absence of the compound).

Increased viability of a retinal cell may be indicated by delayed celldeath or a reduced number of dead or dying cells; maintenance ofstructure and/or morphology; lack of or delayed initiation of apoptosis;delay, inhibition, slowed progression, and/or abrogation of retinalneuronal cell neurodegeneration or delaying or abrogating or preventingthe effects of neuronal cell injury. Methods and techniques fordetermining viability of a retinal cell and thus whether a retinal cellexhibits increased viability are described in greater detail herein andare known to persons skilled in the art.

In certain embodiments, a method is provided for determining whether anamine derivative compound, enhances survival of photoreceptor cells. Onemethod comprises contacting a retinal cell culture system as describedherein with an amine derivative compound under conditions and for a timesufficient to permit interaction between the retinal neuronal cells andthe compound. Enhanced survival (prolonged survival) may be measuredaccording to methods described herein and known in the art, includingdetecting expression of rhodopsin.

The capability of an amine derivative compound to increase retinal cellviability and/or to enhance, promote, or prolong cell survival (that is,to extend the time period in which retinal cells, including retinalneuronal cells, are viable), and/or impair, inhibit, or impededegeneration as a direct or indirect result of the herein describedstress may be determined by any one of several methods known to thoseskilled in the art. For example, changes in cell morphology in theabsence and presence of the compound may be determined by visualinspection such as by light microscopy, confocal microscopy, or othermicroscopy methods known in the art. Survival of cells can also bedetermined by counting viable and/or nonviable cells, for instance.Immunochemical or immunohistological techniques (such as fixed cellstaining or flow cytometry) may be used to identify and evaluatecytoskeletal structure (e.g., by using antibodies specific forcytoskeletal proteins such as glial fibrillary acidic protein,fibronectin, actin, vimentin, tubulin, or the like) or to evaluateexpression of cell markers as described herein. The effect of an aminederivative compound on cell integrity, morphology, and/or survival mayalso be determined by measuring the phosphorylation state of neuronalcell polypeptides, for example, cytoskeletal polypeptides (see, e.g.,Sharma et al., J. Biol. Chem. 274:9600-06 (1999); Li et al., J.Neurosci. 20:6055-62 (2000)). Cell survival or, alternatively celldeath, may also be determined according to methods described herein andknown in the art for measuring apoptosis (for example, annexin Vbinding, DNA fragmentation assays, caspase activation, marker analysis,e.g., poly(ADP-ribose) polymerase (PARP), etc.).

In the vertebrate eye, for example, a mammalian eye, the formation ofA2E is a light-dependent process and its accumulation leads to a numberof negative effects in the eye. These include destabilization of retinalpigment epithelium (RPE) membranes, sensitization of cells to blue-lightdamage, and impaired degradation of phospholipids. Products of theoxidation of A2E (and A2E related molecules) by molecular oxygen(oxiranes) were shown to induce DNA damage in cultured RPE cells. Allthese factors lead to a gradual decrease in visual acuity and eventuallyto vision loss. If reducing the formation of retinals during visionprocesses were possible, this reduction would lead to decreased amountsof A2E in the eye. Without wishing to be bound by theory, decreasedaccumulation of A2E may reduce or delay degenerative processes in theRPE and retina and thus may slow down or prevent vision loss in dry AMDand Stargardt's Disease.

In another embodiment, methods are provided for treating and/orpreventing degenerative diseases and disorders, includingneurodegenerative retinal diseases and ophthalmic diseases, and retinaldiseases and disorders as described herein. A subject in need of suchtreatment may be a human or non-human primate or other animal who hasdeveloped symptoms of a degenerative retinal disease or who is at riskfor developing a degenerative retinal disease.

As described herein a method is provided for treating (which includespreventing or prophylaxis) an ophthalmic disease or disorder byadministrating to a subject a composition comprising a pharmaceuticallyacceptable carrier and an amine derivative compound (e.g., a compoundhaving the structure of Formula (I), and substructures thereof.) Asdescribed herein, a method is provided for enhancing survival ofneuronal cells such as retinal neuronal cells, including photoreceptorcells, and/or inhibiting degeneration of retinal neuronal cells byadministering the pharmaceutical compositions described hereincomprising an amine derivative compound.

Enhanced survival (or prolonged or extended survival) of one or moreretinal cell types in the presence of an amine derivative compoundindicates that the compound may be an effective agent for treatment of adegenerative disease, particularly a retinal disease or disorder, andincluding a neurodegenerative retinal disease or disorder. Cell survivaland enhanced cell survival may be determined according to methodsdescribed herein and known to a skilled artisan including viabilityassays and assays for detecting expression of retinal cell markerproteins. For determining enhanced survival of photoreceptor cells,opsins may be detected, for instance, including the protein rhodopsinthat is expressed by rods.

In another embodiment, the subject is being treated for Stargardt'sdisease or Stargardt's macular degeneration. In Stargardt's disease,which is associated with mutations in the ABCA4 (also called ABCR)transporter, the accumulation of all-trans-retinal has been proposed tobe responsible for the formation of a lipofuscin pigment, A2E, which istoxic towards retinal cells and causes retinal degeneration andconsequently loss of vision.

In yet another embodiment, the subject is being treated for age-relatedmacular degeneration (AMD). In various embodiments, AMD can be wet- ordry-form. In AMD, vision loss primarily occurs when complications latein the disease either cause new blood vessels to grow under the maculaor the macula atrophies. Without intending to be bound by any particulartheory, the accumulation of all-trans-retinal has been proposed to beresponsible for the formation of a lipofuscin pigment,N-retinylidene-N-retinylethanolamine (A2E) and A2E related molecules,which are toxic towards RPE and retinal cells and cause retinaldegeneration and consequently loss of vision.

A neurodegenerative retinal disease or disorder for which the compoundsand methods described herein may be used for treating, curing,preventing, ameliorating the symptoms of, or slowing, inhibiting, orstopping the progression of, is a disease or disorder that leads to oris characterized by retinal neuronal cell loss, which is the cause ofvisual impairment. Such a disease or disorder includes but is notlimited to age-related macular degeneration (including dry-form andwet-form of macular degeneration) and Stargardt's macular dystrophy.

Age-related macular degeneration as described herein is a disorder thataffects the macula (central region of the retina) and results in thedecline and loss of central vision. Age-related macular degenerationoccurs typically in individuals over the age of 55 years. The etiologyof age-related macular degeneration may include both environmentalinfluences and genetic components (see, e.g., Lyengar et al., Am. J.Hum. Genet. 74:20-39 (2004) (Epub 2003 Dec. 19); Kenealy et al., Mol.Vis. 10:57-61 (2004); Gorin et al., Mol. Vis. 5:29 (1999)). More rarely,macular degeneration occurs in younger individuals, including childrenand infants, and generally, these disorders results from a geneticmutation. Types of juvenile macular degeneration include Stargardt'sdisease (see, e.g., Glazer et al., Ophthalmol. Clin. North Am.15:93-100, viii (2002); Weng et al., Cell 98:13-23 (1999)); Doyne'shoneycomb retinal dystrophy (see, e.g., Kermani et al., Hum. Genet.104:77-82 (1999)); Sorsby's fundus dystrophy, Malattia Levintinese,fundus flavimaculatus, and autosomal dominant hemorrhagic maculardystrophy (see also Seddon et al., Ophthalmology 108:2060-67 (2001);Yates et al., J. Med. Genet. 37:83-7 (2000); Jaakson et al., Hum. Mutat.22:395-403 (2003)). Geographic atrophy of the RPE is an advanced form ofnon-neovascular dry-type age-related macular degeneration, and isassociated with atrophy of the choriocapillaris, RPE, and retina.

Stargardt's macular degeneration, a recessive inherited disease, is aninherited blinding disease of children. The primary pathologic defect inStargardt's disease is also an accumulation of toxic lipofuscin pigmentssuch as A2E in cells of the retinal pigment epithelium (RPE). Thisaccumulation appears to be responsible for the photoreceptor death andsevere visual loss found in Stargardt's patients. The compoundsdescribed herein may slow the synthesis of 11-cis-retinaldehyde (11 cRALor retinal) and regeneration of rhodopsin by inhibiting isomerase in thevisual cycle. Light activation of rhodopsin results in its release ofall-trans-retinal, which constitutes the first reactant in A2Ebiosynthesis. Treatment with amine derivative compounds may inhibitlipofuscin accumulation and thus delay the onset of visual loss inStargardt's and AMD patients without toxic effects that would precludetreatment with an amine derivative compound. The compounds describedherein may be used for effective treatment of other forms of retinal ormacular degeneration associated with lipofuscin accumulation.

Administration of an amine derivative compound to a subject can preventformation of the lipofuscin pigment, A2E (and A2E related molecules),that is toxic towards retinal cells and causes retinal degeneration. Incertain embodiments, administration of an amine derivative compound canlessen the production of waste products, e.g., lipofuscin pigment, A2E(and A2E related molecules), ameliorate the development of AMD (e.g.,dry-form) and Stargardt's disease, and reduce or slow vision loss (e.g.,choroidal neovascularization and/or chorioretinal atrophy).

In previous studies, with 13-cis-retinoic acid (Accutane® orIsotretinoin), a drug commonly used for the treatment of acne and aninhibitor of 11-cis-retinol dehydrogenase, has been administered topatients to prevent A2E accumulation in the RPE. However, a majordrawback in this proposed treatment is that 13-cis-retinoic acid caneasily isomerize to all-trans-retinoic acid. All-trans-retinoic acid isa very potent teratogenic compound that adversely affects cellproliferation and development. Retinoic acid also accumulates in theliver and may be a contributing factor in liver diseases.

In yet other embodiments, an amine derivative compound is administeredto a subject such as a human with a mutation in the ABCA4 transporter inthe eye. The amine derivative compound can also be administered to anaging subject. As used herein, an aging human subject is typically atleast 45, or at least 50, or at least 60, or at least 65 years old. InStargardt's disease, which is associated with mutations in the ABCA4transporter, the accumulation of all-trans-retinal has been proposed tobe responsible for the formation of a lipofuscin pigment, A2E (and A2Erelated molecules), that is toxic towards retinal cells and causesretinal degeneration and consequently loss of vision. Without wishing tobe bound by theory, an amine derivative compound described herein may bea strong inhibitor of an isomerase involved in the visual cycle.Treating patients with an amine derivative compound as described hereinmay prevent or slow the formation of A2E (and A2E related molecules) andcan have protective properties for normal vision.

In other certain embodiments, one or more of the compounds describedherein may be used for treating other ophthalmic diseases or disorders,for example, glaucoma, retinal detachment, hemorrhagic retinopathy,retinitis pigmentosa, an inflammatory retinal disease, proliferativevitreoretinopathy, retinal dystrophy, hereditary optic neuropathy,Sorsby's fundus dystrophy, uveitis, a retinal injury, opticalneuropathy, and retinal disorders associated with otherneurodegenerative diseases such as Alzheimer's disease, multiplesclerosis, Parkinson's disease or other neurodegenerative diseases thataffect brain cells, a retinal disorder associated with viral infection,or other conditions such as AIDS. A retinal disorder also includes lightdamage to the retina that is related to increased light exposure (i.e.,overexposure to light), for example, accidental strong or intense lightexposure during surgery; strong, intense, or prolonged sunlightexposure, such as at a desert or snow covered terrain; during combat,for example, when observing a flare or explosion or from a laser device,and the like. Retinal diseases can be of degenerative ornon-degenerative nature. Non-limiting examples of degenerative retinaldiseases include age-related macular degeneration, and Stargardt'smacular dystrophy. Examples of non-degenerative retinal diseases includebut are not limited hemorrhagic retinopathy, retinitis pigmentosa, opticneuropathy, inflammatory retinal disease, diabetic retinopathy, diabeticmaculopathy, retinal blood vessel occlusion, retinopathy of prematurity,or ischemia reperfusion related retinal injury, proliferativevitreoretinopathy, retinal dystrophy, hereditary optic neuropathy,Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorderassociated with Alzheimer's disease, a retinal disorder associated withmultiple sclerosis, a retinal disorder associated with Parkinson'sdisease, a retinal disorder associated with viral infection, a retinaldisorder related to light overexposure, and a retinal disorderassociated with AIDS.

In other certain embodiments, at least one of the compounds describedherein may be used for treating, curing, preventing, ameliorating thesymptoms of, or slowing, inhibiting, or stopping the progression of,certain ophthalmic diseases and disorders including but not limited todiabetic retinopathy, diabetic maculopathy, diabetic macular edema,retinal ischemia, ischemia-reperfusion related retinal injury, andretinal blood vessel occlusion (including venous occlusion and arterialocclusion).

Diabetic retinopathy is a leading cause of blindness in humans and is acomplication of diabetes. Diabetic retinopathy occurs when diabetesdamages blood vessels inside the retina. Non-proliferative retinopathyis a common, usually mild form that generally does not interfere withvision. Abnormalities are limited to the retina, and vision is impairedonly if the macula is involved. If left untreated retinopathy canprogress to proliferative retinopathy, the more serious form of diabeticretinopathy. Proliferative retinopathy occurs when new blood vesselsproliferate in and around the retina. Consequently, bleeding into thevitreous, swelling of the retina, and/or retinal detachment may occur,leading to blindness.

Other ophthalmic diseases and disorders that may be treated using themethods and compositions described herein include diseases, disorders,and conditions that are associated with, exacerbated by, or caused byischemia in the retina. Retinal ischemia includes ischemia of the innerretina and the outer retina. Retinal ischemia can occur from eitherchoroidal or retinal vascular diseases, such as central or branchretinal vision occlusion, collagen vascular diseases andthrombocytopenic purpura. Retinal vasculitis and occlusion is seen withEales disease and systemic lupus erythematosus.

Retinal ischemia may be associated with retinal blood vessel occlusion.In the United States, both branch and central retinal vein occlusionsare the second most common retinal vascular diseases after diabeticretinopathy.

About 7% to 10% of patients who have retinal venous occlusive disease inone eye eventually have bilateral disease.

Visual field loss commonly occurs from macular edema, ischemia, orvitreous hemorrhage secondary to disc or retinal neovascularizationinduced by the release of vascular endothelial growth factor.

Arteriolosclerosis at sites of retinal arteriovenous crossings (areas inwhich arteries and veins share a common adventitial sheath) causesconstriction of the wall of a retinal vein by a crossing artery. Theconstriction results in thrombus formation and subsequent occlusion ofthe vein. The blocked vein may lead to macular edema and hemorrhagesecondary to breakdown in the blood-retina barrier in the area drainedby the vein, disruption of circulation with turbulence in venous flow,endothelial damage, and ischemia. Clinically, areas of ischemic retinaappear as feathery white patches called cotton-wool spots.

Branch retinal vein occlusions with abundant ischemia cause acutecentral and paracentral visual field loss corresponding to the locationof the involved retinal quadrants. Retinal neovascularization due toischemia may lead to vitreous hemorrhage and subacute or acute visionloss.

Two types of central retinal vein occlusion, ischemic and nonischemic,may occur depending on whether widespread retinal ischemia is present.Even in the nonischemic type, the macula may still be ischemic.Approximately 25% central retinal vein occlusion is ischemic. Diagnosisof central retinal vein occlusion can usually be made on the basis ofcharacteristic ophthalmoscopic findings, including retinal hemorrhage inall quadrants, dilated and tortuous veins, and cotton-wool spots.Macular edema and foveal ischemia can lead to vision loss. Extracellularfluid increases interstitial pressure, which may result in areas ofretinal capillary closure (i.e., patchy ischemic retinal whitening) orocclusion of a cilioretinal artery.

Patients with ischemic central retinal vein occlusion are more likely topresent with a sudden onset of vision loss and have visual acuity ofless than 20/200, a relative afferent pupillary defect, abundantintraretinal hemorrhages, and extensive nonperfusion on fluoresceinangiography. The natural history of ischemic central retinal veinocclusion is associated with poor outcomes: eventually, approximatelytwo-thirds of patients who have ischemic central retinal vein occlusionwill have ocular neovascularization and one-third will have neovascularglaucoma. The latter condition is a severe type of glaucoma that maylead to rapid visual field and vision loss, epithelial edema of thecornea with secondary epithelial erosion and predisposition to bacterialkeratitis, severe pain, nausea and vomiting, and, eventually, phthisisbulbi (atrophy of the globe with no light perception).

As used herein, a patient (or subject) may be any mammal, including ahuman, that may have or be afflicted with a neurodegenerative disease orcondition, including an ophthalmic disease or disorder, or that may befree of detectable disease. Accordingly, the treatment may beadministered to a subject who has an existing disease, or the treatmentmay be prophylactic, administered to a subject who is at risk fordeveloping the disease or condition.

Treating or treatment refers to any indicia of success in the treatmentor amelioration of an injury, pathology or condition, including anyobjective or subjective parameter such as abatement; remission;diminishing of symptoms or making the injury, pathology, or conditionmore tolerable to the patient; slowing in the rate of degeneration ordecline; making the final point of degeneration less debilitating; orimproving a subject's physical or mental well-being.

The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination.Accordingly, the term “treating” includes the administration of thecompounds or agents described herein to treat pain, hyperalgesia,allodynia, or nociceptive events and to prevent or delay, to alleviate,or to arrest or inhibit development of the symptoms or conditionsassociated with pain, hyperalgesia, allodynia, nociceptive events, orother disorders. The term “therapeutic effect” refers to the reduction,elimination, or prevention of the disease, symptoms of the disease, orsequelae of the disease in the subject. Treatment also includesrestoring or improving retinal neuronal cell functions (includingphotoreceptor function) in a vertebrate visual system, for example, suchas visual acuity and visual field testing etc., as measured over time(e.g., as measured in weeks or months). Treatment also includesstabilizing disease progression (i.e., slowing, minimizing, or haltingthe progression of an ophthalmic disease and associated symptoms) andminimizing additional degeneration of a vertebrate visual system.Treatment also includes prophylaxis and refers to the administration ofan amine derivative compound to a subject to prevent degeneration orfurther degeneration or deterioration or further deterioration of thevertebrate visual system of the subject and to prevent or inhibitdevelopment of the disease and/or related symptoms and sequelae.

Various methods and techniques practiced by a person skilled in themedical and ophthalmological arts to determine and evaluate a diseasestate and/or to monitor and assess a therapeutic regimen include, forexample, fluorescein angiogram, fundus photography, indocyanine greendye tracking of the choroidal circulatory system, opthalmoscopy, opticalcoherence tomography (OCT), and visual acuity testing.

A fluorescein angiogram involves injecting a fluorescein dyeintravenously and then observing any leakage of the dye as it circulatesthrough the eye. Intravenous injection of indocyanine green dye may alsobe used to determine if vessels in the eye are compromised, particularlyin the choroidal circulatory system that is just behind the retina.Fundus photography may be used for examining the optic nerve, macula,blood vessels, retina, and the vitreous. Microaneurysms are visiblelesions in diabetic retinopathy that may be detected in digital fundusimages early in the disease (see, e.g., U.S. Patent ApplicationPublication No. 2007/0002275). An ophthalmoscope may be used to examinethe retina and vitreous. Opthalmoscopy is usually performed with dilatedpupils, to allow the best view inside the eye. Two types ofophthalmoscopes may be used: direct and indirect. The directophthalmoscope is generally used to view the optic nerve and the centralretina. The periphery, or entire retina, may be viewed by using anindirect ophthalmoscope. Optical coherence tomography (OCT) produceshigh resolution, high speed, non-invasive, cross-sectional images ofbody tissue. OCT is noninvasive and provides detection of microscopicearly signs of disruption in tissues.

A subject or patient refers to any vertebrate or mammalian patient orsubject to whom the compositions described herein can be administered.The term “vertebrate” or “mammal” includes humans and non-humanprimates, as well as experimental animals such as rabbits, rats, andmice, and other animals, such as domestic pets (such as cats, dogs,horses), farm animals, and zoo animals. Subjects in need of treatmentusing the methods described herein may be identified according toaccepted screening methods in the medical art that are employed todetermine risk factors or symptoms associated with an ophthalmic diseaseor condition described herein or to determine the status of an existingophthalmic disease or condition in a subject. These and other routinemethods allow the clinician to select patients in need of therapy usingthe methods and formulations described herein.

V. PHARMACEUTICAL COMPOSITIONS

In certain embodiments, an amine derivative compound may be administeredas a pure chemical. In other embodiments, the amine derivative compoundcan be combined with a pharmaceutical carrier (also referred to hereinas a pharmaceutically acceptable excipient (i.e., a pharmaceuticallysuitable and acceptable carrier, diluent, etc., which is a non-toxic,inert material that does not interfere with the activity of the activeingredient)) selected on the basis of a chosen route of administrationand standard pharmaceutical practice as described, for example, inRemington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)), the disclosure of which is herebyincorporated herein by reference, in its entirety.

Accordingly, provided herein is a pharmaceutical composition comprisingone or more amine derivative compounds, or a stereoisomer, tautomer,prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salthydrate, N-oxide or isomorphic crystalline form thereof, of a compounddescribed herein, together with one or more pharmaceutically acceptablecarriers and, optionally, other therapeutic and/or prophylacticingredients. The carrier(s) (or excipient(s)) is acceptable or suitableif the carrier is compatible with the other ingredients of thecomposition and not deleterious to the recipient (i.e., the subject) ofthe composition. A pharmaceutically acceptable or suitable compositionincludes an ophthalmologically suitable or acceptable composition.

In one embodiment is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (A) ortautomer, stereoisomer, geometric isomer, or pharmaceutically acceptablesolvate, hydrate, salt, N-oxide or prodrug thereof:

wherein,

-   Z is a bond, —C(R¹)(R²)—, —C(R⁹)(R¹⁰)—C(R¹)(R²)—, —X—C(R³¹)(R³²)—,    —C(R⁹)(R¹⁰)—C(R¹)(R²)—C(R³⁶)(R³⁷)— or —X—C(R³¹)(R³²)—C(R¹)(R²)—;-   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R³⁰)—, —C(═O)—, —C(═CH₂)—,    —C(═N—NR³⁵)—, or —C(═N—OR³⁵)—;-   G is selected from —C(R⁴¹)₂—C(R⁴¹)₂—R⁴⁰, —C(R⁴²)₂—S—R⁴⁰,    —C(R⁴²)₂—SO—R⁴⁰, —C(R⁴²)₂—SO₂—R⁴⁰, —C(R⁴²)₂—O—R⁴⁰,    —C(R⁴²)₂—N(R⁴²)—R⁴⁰, —C(═O)—N(R⁴²)—R⁴⁰;-   R⁴⁰ is selected from —C(R¹⁶)(R¹⁷)(R¹⁸), aryl, or heteroaryl;-   each R⁴¹ is independently selected from hydrogen, hydroxy, OR⁶,    alkyl, or two R⁴¹ groups together may form an oxo;-   each R⁴² is independently selected from hydrogen or alkyl;-   R¹ and R² are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or R¹ and R² together form    an oxo;-   R³¹ and R³² are each independently selected from hydrogen, C₁-C₅    alkyl, or fluoroalkyl;-   R³⁶ and R³⁷ are each independently selected from hydrogen, halogen,    C₁-C₅ alkyl, fluoroalkyl, —OR⁶ or —NR⁷R⁸; or    -   R³⁶ and R³⁷ together form an oxo; or optionally, R³⁶ and R¹        together form a direct bond to provide a double bond; or        optionally, R³⁶ and R¹ together form a direct bond, and R³⁷ and        R² together form a direct bond to provide a triple bond;-   R³ and R⁴ are each independently selected from hydrogen, alkyl,    alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached    heterocyclyl; or R³ and R⁴ together with the carbon atom to which    they are attached, form a carbocyclyl or heterocyclyl; or R³ and R⁴    together form an imino;-   R⁷ and R⁸ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R¹³, SO₂R¹³, CO₂R¹³ or SO₂NR²⁴R²⁵;    or R⁷ and R⁸ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   R⁹ and R¹⁰ are each independently selected from hydrogen, halogen,    alkyl, fluoroalkyl, —OR¹⁹, —NR²⁰R²¹ or carbocyclyl; or R⁹ and R¹⁰    form an oxo; or optionally, R⁹ and R¹ together form a direct bond to    provide a double bond; or optionally, R⁹ and R¹ together form a    direct bond, and R¹⁰ and R² together form a direct bond to provide a    triple bond;-   R¹¹ and R¹² are each independently selected from hydrogen, alkyl,    carbocyclyl, —C(═O)R²³, —C(NH)NH₂, SO₂R²³, CO₂R²³ or SO₂NR²⁸R²⁹; or    R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl;-   each R¹³, R²² and R²³ is independently selected from alkyl,    heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or    heterocyclyl;-   R⁶, R¹⁹, R³⁰, R³⁴ and R³⁵ are each independently hydrogen or alkyl;-   R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,    carbocyclyl, heterocyclyl, —C(═O)R²², SO₂R²², CO₂R²² or SO₂NR²⁶R²⁷;    or R²⁰ and R²¹ together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   each R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ is independently selected from    hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl    or heterocyclyl;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen, alkyl,    halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl; or    R¹⁶ and R¹⁷, together with the carbon to which they are attached    form a carbocyclyl or heterocycle;-   R¹⁸ is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or    fluoroalkyl;-   each R³³ is independently selected from halogen, OR³⁴, alkyl, or    fluoroalkyl; and n is 0, 1, 2, 3, or 4; with the provision that G is    not an unsubstituted normal alkyl and the provision that the    compound of Formula A is not:

Various embodiments further provide pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and a compound ofFormula (I):

as a tautomer or a mixture of tautomers, or as a pharmaceuticallyacceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:

-   R¹ and R² are each the same or different and independently hydrogen,    halogen, C₁-C₅ alkyl, fluoroalkyl, —OR⁶, or —NR⁷R⁸; or R¹ and R²    form an oxo;-   R³ and R⁴ are each the same or different and independently hydrogen    or alkyl;-   R⁵ is C₅-C₁₅ alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or    carbocyclylalkyl;-   R⁶ is hydrogen or alkyl;-   R⁷ and R⁸ are each the same or different and independently hydrogen,    alkyl, carbocyclyl, or —C(═O)R¹³; or-   R⁷ and R⁸, together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; X is —C(R⁹)(R¹⁰)— or —O—;-   R⁹ and R¹⁰ are each the same or different and independently    hydrogen, halogen, alkyl, fluoroalkyl, —OR⁶, —NR⁷R⁸ or carbocyclyl;    or R⁹ and R¹⁰ form an oxo;-   R¹¹ and R¹² are each the same or different and independently    hydrogen, alkyl, or —C(═O)R¹³; or-   R¹¹ and R¹², together with the nitrogen atom to which they are    attached, form an N-heterocyclyl; and-   R¹³ is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or    heterocyclyl.

A pharmaceutical composition (e.g., for oral administration or deliveryby injection, or combined devices, or for application as an eye drop)may be in the form of a liquid or solid. A liquid pharmaceuticalcomposition may include, for example, one or more of the following:sterile diluents such as water for injection, saline solution,preferably physiological saline, Ringer's solution, isotonic sodiumchloride, fixed oils that may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents; antioxidants; chelating agents; buffers and agentsfor the adjustment of tonicity such as sodium chloride or dextrose.

A parenteral preparation can be enclosed in ampules, disposable syringesor multiple dose vials made of glass or plastic. Physiological saline iscommonly used as an excipient, and an injectable pharmaceuticalcomposition or a composition that is delivered ocularly is preferablysterile.

At least one amine derivative compound can be administered to human orother nonhuman vertebrates. In certain embodiments, the compound issubstantially pure, in that it contains less than about 5% or less thanabout 1%, or less than about 0.1%, of other organic small molecules,such as contaminating intermediates or by-products that are created, forexample, in one or more of the steps of a synthesis method. In otherembodiments, a combination of one or more amine derivative compounds canbe administered.

An amine derivative compound can be delivered to a subject by anysuitable means, including, for example, orally, parenterally,intraocularly, intravenously, intraperitoneally, intranasally (or otherdelivery methods to the mucous membranes, for example, of the nose,throat, and bronchial tubes), or by local administration to the eye, orby an intraocular or periocular device. Modes of local administrationcan include, for example, eye drops, intraocular injection or periocularinjection. Periocular injection typically involves injection of thesynthetic isomerization inhibitor, i.e., amine derivative compound asdescribed herein, under the conjunctiva or into the Tennon's space(beneath the fibrous tissue overlying the eye). Intraocular injectiontypically involves injection of the amine derivative compound into thevitreous. In certain embodiments, the administration is non-invasive,such as by eye drops or oral dosage form, or as a combined device.

An amine derivative compound can be formulated for administration usingpharmaceutically acceptable (suitable) carriers or vehicles as well astechniques routinely used in the art. A pharmaceutically acceptable orsuitable carrier includes an ophthalmologically suitable or acceptablecarrier. A carrier is selected according to the solubility of the aminederivative compound. Suitable ophthalmological compositions includethose that are administrable locally to the eye, such as by eye drops,injection or the like. In the case of eye drops, the formulation canalso optionally include, for example, ophthalmologically compatibleagents such as isotonizing agents such as sodium chloride, concentratedglycerin, and the like; buffering agents such as sodium phosphate,sodium acetate, and the like; surfactants such as polyoxyethylenesorbitan mono-oleate (also referred to as Polysorbate 80), polyoxylstearate 40, polyoxyethylene hydrogenated castor oil, and the like;stabilization agents such as sodium citrate, sodium edentate, and thelike; preservatives such as benzalkonium chloride, parabens, and thelike; and other ingredients. Preservatives can be employed, for example,at a level of from about 0.001 to about 1.0% weight/volume. The pH ofthe formulation is usually within the range acceptable to ophthalmologicformulations, such as within the range of about pH 4 to 8, or pH 5 to 7,or pH 6 to 7, or pH 4 to 7, or pH 5 to 8, or pH 6 to 8, or pH 4 to 6, orpH 5 to 6, or pH 7 to 8.

In additional embodiments, the compositions described herein furthercomprise cyclodextrins. Cyclodextrins are cyclic oligosaccharidescontaining 6, 7, or 8 glucopyranose units, referred to asα-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin respectively.Cyclodextrins have been found to be particularly useful inpharmaceutical formulations. Cyclodextrins have a hydrophilic exterior,which enhances water-soluble, and a hydrophobic interior which forms acavity. In an aqueous environment, hydrophobic portions of othermolecules often enter the hydrophobic cavity of cyclodextrin to forminclusion compounds. Additionally, cyclodextrins are also capable ofother types of nonbonding interactions with molecules that are notinside the hydrophobic cavity. Cyclodextrins have three free hydroxylgroups for each glucopyranose unit, or 18 hydroxyl groups onα-cyclodextrin, 21 hydroxyl groups on β-cyclodextrin, and 24 hydroxylgroups on γ-cyclodextrin. One or more of these hydroxyl groups can bereacted with any of a number of reagents to form a large variety ofcyclodextrin derivatives. Some of the more common derivatives ofcyclodextrin are hydroxypropyl ethers, sulfonates, and sulfoalkylethers.Shown below is the structure of β-cyclodextrin and thehydroxypropyl-β-cyclodextrin (HPβCD).

The use of cyclodextrins in pharmaceutical compositions is well known inthe art as cyclodextrins and cyclodextrin derivatives are often used toimprove the solubility of a drug. Inclusion compounds are involved inmany cases of enhanced solubility; however other interactions betweencyclodextrins and insoluble compounds can also improve solubility.Hydroxypropyl-β-cyclodextrin (HPβCD) is commercially available as apyrogen free product. It is a nonhygroscopic white powder that readilydissolves in water. HPβCD is thermally stable and does not degrade atneutral pH.

Ophthalmic formulations utilizing cyclodextrins have been disclosed. Forexample, U.S. Pat. No. 5,227,372 discloses methods related to retainingophthalmological agents in ocular tissues. US Patent ApplicationPublication 2007/0149480 teaches the use of cyclodextrins to prepareophthalmic formulations of a small molecule kinase inhibitor with poorwater solubility.

The concentration of the cyclodextrin used in the compositions andmethods disclosed herein can vary according to the physiochemicalproperties, pharmacokinetic properties, side effect or adverse events,formulation considerations, or other factors associated with thetherapeutically active agent, or a salt or prodrug thereof. Theproperties of other excipients in a composition may also be important.Thus, the concentration or amount of cyclodextrin used in accordancewith the compositions and methods disclosed herein can vary. In certaincompositions, the concentration of the cyclodextrin is from 10% to 25%.

For injection, the amine derivative compound can be provided in aninjection grade saline solution, in the form of an injectable liposomesolution, slow-release polymer system or the like. Intraocular andperiocular injections are known to those skilled in the art and aredescribed in numerous publications including, for example, Spaeth, Ed.,Ophthalmic Surgery: Principles of Practice, W. B. Sanders Co.,Philadelphia, Pa., 85-87, 1990.

For delivery of a composition comprising at least one of the compoundsdescribed herein via a mucosal route, which includes delivery to thenasal passages, throat, and airways, the composition may be delivered inthe form of an aerosol. The compound may be in a liquid or powder formfor intramucosal delivery. For example, the composition may be deliveredvia a pressurized aerosol container with a suitable propellant, such asa hydrocarbon propellant (e.g., propane, butane, isobutene). Thecomposition may be delivered via a non-pressurized delivery system suchas a nebulizer or atomizer.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. (See, e.g., Remington: The Science and Practiceof Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

The amine derivative compounds described herein may be formulated forsustained or slow-release. Such compositions may generally be preparedusing well known technology and administered by, for example, oral,periocular, intraocular, rectal or subcutaneous implantation, or byimplantation at the desired target site. Sustained-release formulationsmay contain an agent dispersed in a carrier matrix and/or containedwithin a reservoir surrounded by a rate controlling membrane. Excipientsfor use within such formulations are biocompatible, and may also bebiodegradable; preferably the formulation provides a relatively constantlevel of active component release. The amount of active compoundcontained within a sustained-release formulation depends upon the siteof implantation, the rate and expected duration of release, and thenature of the condition to be treated or prevented.

Systemic drug absorption of a drug or composition administered via anocular route is known to those skilled in the art (see, e.g., Lee etal., Int. J. Pharm. 233:1-18 (2002)). In one embodiment, an aminederivative compound is delivered by a topical ocular delivery method(see, e.g., Curr. Drug Metab. 4:213-22 (2003)). The composition may bein the form of an eye drop, salve, or ointment or the like, such as,aqueous eye drops, aqueous ophthalmic suspensions, non-aqueous eyedrops, and non-aqueous ophthalmic suspensions, gels, ophthalmicointments, etc. For preparing a gel, for example, carboxyvinyl polymer,methyl cellulose, sodium alginate, hydroxypropyl cellulose, ethylenemaleic anhydride polymer and the like can be used.

The dose of the composition comprising at least one of the aminederivative compounds described herein may differ, depending upon thepatient's (e.g., human) condition, that is, stage of the disease,general health status, age, and other factors that a person skilled inthe medical art will use to determine dose. When the composition is usedas eye drops, for example, one to several drops per unit dose,preferably 1 or 2 drops (about 50 μl per 1 drop), may be applied about 1to about 6 times daily.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity). For prophylactic use, a dose should be sufficient to prevent,delay the onset of, or diminish the severity of a disease associatedwith neurodegeneration of retinal neuronal cells and/or degeneration ofother mature retinal cells such as RPE cells. Optimal doses maygenerally be determined using experimental models and/or clinicaltrials. The optimal dose may depend upon the body mass, weight, or bloodvolume of the patient.

The doses of the amine derivative compounds can be suitably selecteddepending on the clinical status, condition and age of the subject,dosage form and the like. In the case of eye drops, an amine derivativecompound can be administered, for example, from about 0.01 mg, about 0.1mg, or about 1 mg, to about 25 mg, to about 50 mg, to about 90 mg persingle dose. Eye drops can be administered one or more times per day, asneeded. In the case of injections, suitable doses can be, for example,about 0.0001 mg, about 0.001 mg, about 0.01 mg, or about 0.1 mg to about10 mg, to about 25 mg, to about 50 mg, or to about 90 mg of the aminederivative compound, one to seven times per week. In other embodiments,about 1.0 to about 30 mg of the amine derivative compound can beadministered one to seven times per week.

Oral doses can typically range from 1.0 to 1000 mg, one to four times,or more, per day. An exemplary dosing range for oral administration isfrom 10 to 250 mg one to three times per day. If the composition is aliquid formulation, the composition comprises at least 0.1% activecompound at particular mass or weight (e.g., from 1.0 to 1000 mg) perunit volume of carrier, for example, from about 2% to about 60%.

In certain embodiments, at least one amine derivative compound describedherein may be administered under conditions and at a time that inhibitsor prevents dark adaptation of rod photoreceptor cells. In certainembodiments, the compound is administered to a subject at least 30minutes (half hour), 60 minutes (one hour), 90 minutes (1.5 hour), or120 minutes (2 hours) prior to sleeping. In certain embodiments, thecompound may be administered at night before the subject sleeps. Inother embodiments, a light stimulus may be blocked or removed during theday or under normal light conditions by placing the subject in anenvironment in which light is removed, such as placing the subject in adarkened room or by applying an eye mask over the eyes of the subject.When the light stimulus is removed in such a manner or by other meanscontemplated in the art, the agent may be administered prior tosleeping.

The doses of the compounds that may be administered to prevent orinhibit dark adaptation of a rod photoreceptor cell can be suitablyselected depending on the clinical status, condition and age of thesubject, dosage form and the like. In the case of eye drops, thecompound (or the composition comprising the compound) can beadministered, for example, from about 0.01 mg, about 0.1 mg, or about 1mg, to about 25 mg, to about 50 mg, to about 90 mg per single dose. Inthe case of injections, suitable doses can be, for example, about 0.0001mg, about 0.001 mg, about 0.01 mg, or about 0.1 mg to about 10 mg, toabout 25 mg, to about 50 mg, or to about 90 mg of the compound,administered any number of days between one to seven days per week priorto sleeping or prior to removing the subject from all light sources. Incertain other embodiments, for administration of the compound by eyedrops or injection, the dose is between 1-10 mg (compound)/kg (bodyweight of subject) (i.e., for example, 80-800 mg total per dose for asubject weighing 80 kg). In other embodiments, about 1.0 to about 30 mgof compound can be administered one to seven times per week. Oral dosescan typically range from about 1.0 to about 1000 mg, administered anynumber of days between one to seven days per week. An exemplary dosingrange for oral administration is from about 10 to about 800 mg once perday prior to sleeping. In other embodiments, the composition may bedelivered by intravitreal administration.

Also provided are methods of manufacturing the compounds andpharmaceutical compositions described herein. A composition comprising apharmaceutically acceptable excipient or carrier and at least one of theamine derivative compounds described herein may be prepared bysynthesizing the compound according to any one of the methods describedherein or practiced in the art and then formulating the compound with apharmaceutically acceptable carrier. Formulation of the composition willbe appropriate and dependent on several factors, including but notlimited to, the delivery route, dose, and stability of the compound.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

EXAMPLES

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Flash column chromatography and thin layer chromatography (TLC) wereperformed on silica gel unless otherwise noted. Proton and carbonnuclear magnetic resonance spectra were obtained with a Varian VnmrS 400at 400 MHz for proton and 100 MHz for carbon, or with a Bruker AMX 500or 300 spectrometers at 500 or 300 MHz for proton and 125 or 75 MHz forcarbon, as noted. Spectra are given in ppm (δ) and coupling constants,J, are reported in Hertz. For proton spectra either tetramethylsilanewas used as an internal standard or the solvent peak was used as thereference peak. For carbon spectra the solvent peak was used as thereference. Chiral HPLC analysis was performed using a Chiralpak IAcolumn (4.6 mm×250 mm, 5 g) with diode array detection. The flow ratewas 1 mL/min.

Analytical HPLC Methods

HPLC analyses were obtained using a Hypersil BDS C18 column (250×4.6 mm,Phenomenex) with detection at 254 nm using a standard solvent gradientprogram (Method 1).

ANALYTICAL HPLC METHOD 1: Time Flow (min) (mL/min) % A % B 0.0 1.0 70.030.0 15.0 1.0 0.0 100.0 20.0 1.0 0.0 100.0 Analytical HPLC Method 2:Time Flow (min) (mL/min) % A % B 0.0 1.0 90.0 10.0 10.0 1.0 5.0 95.0 A =Water with 0.05% Trifluoroacetic Acid B = Acetonitrilewith 0.05 %Trifluoroacetic Acid A = Water with 0.05% Trifluoroacetic Acid B =Acetonitrile with 0.05% Trifluoroacetic Acid Column = Gemini C18, 4.6 ×150 mm, 5 μ

Preparative HPLC Methods

Preparative HPLC was performed using a YMC ODA-A column (500 mm×30mm×10μ) at ambient temperature with detection at 220 nm using aninjection volume of 5 mL and a standard solvent gradient program (Method1P or 2P).

PREPARATIVE HPLC METHOD 1P: Time Flow (min) (mL/min) % A % B 0.0 30 9010 5.0 30 90 10 25 30 20 80 35 30 20 80 A = Water with 0.05%Trifluoroacetic Acid B = Acetonitrilewith 0.05% Trifluoroacetic Acid*PREPARATIVE HPLC METHOD 2P: Time (mm) Flow % A % B 0.0 30 90 10 5.0 3090 10 25 30 20 80 35 30 20 80 A = Water B = Acetonitrile PREPARATIVEHPLC METHOD 3P: Time Flow (min) (mL/min) % A % B 0.0 30 50 50 5.0 30 5050 Time Flow (min) (mL/min) % A % B 25 30  0 100 35 30  0 100 A = Waterwith 0.05% Trifluoroacetic Acid B = Acetonitrilewith 0.05%Trifluoroacetic AcidSolvents for sample preparation: Methanol, Acetonitrile,Acetonitrile:Methanol(1:1)

Time Flow (min) (mL/min) % A % B 0.0 30 90 10 5.0 30 90 10 25 30 20 8035 30 20 80 A = Water B = AcetonitrileSolvents for sample preparation: Methanol, Acetonitrile,Acetonitrile:Methanol(1:1)

Example 1 Preparation of3-(3-(2,6-dimethylphenethyl)phenyl)propan-1-amine

3-(3-(2,6-Dimethylphenethyl)phenyl)propan-1-amine was prepared followingthe method shown in Scheme 1.

Step 1: To a stirred solution of 2,6-dimethylbenzoic acid (1) (10.0 g,66.6 mmol) in THF (100 mL) at 0° C. was added borane-THF complex (80 mLof a 1M solution in THF, 80.0 mmol) dropwise over 20 min and then thereaction mixture was warmed to room temperature. After 64 h the reactionmixture was quenched by slow addition of MeOH (70 mL) and the resultingsolution was concentrated under reduced pressure. The residue wassuspended in EtOAc (300 mL) and washed with water and brine. The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure togive alcohol 2 as a white solid. Yield (9.10 g, >99%): ¹H NMR (500 MHz,CDCl₃) δ 7.03-7.13 (m, 3H), 4.74 (d, J=5.1 Hz, 2H), 2.43 (s, 6H), 1.28(t, J=5.2 Hz, 1H); ESI MS m/z 119 [M+H−H₂O]⁺.

Step 2: To a stirred solution of triphenylphosphine hydrobromide (22.0g, 64.0 mmol) in MeOH (80 mL) was added a solution of alcohol 2 (8.72 g,64.0 mmol) in MeOH (70 mL) and the reaction mixture was stirred at roomtemperature for 48 h. The reaction solution was concentrated underreduced pressure and the residue was triturated with a mixture ofacetone (20 mL) and diethyl ether (50 mL). The precipitate was collectedby vacuum filtration, washed with diethyl ether (30 mL) and hexanes (30mL), and concentrated under reduced pressure to providetriphenylphosphine salt 3 as a white solid. Yield (23.0 g, 78%): mp240-246° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.51-7.95 (m, 15H), 7.15 (dt,J=7.7, 2.6 Hz, 1H), 6.96 (d, J=7.7 Hz, 2H), 4.94 (d, J=14.6 Hz, 2H),1.76 (s, 6H); ESI MS m/z 381 [M−Br]⁺; HPLC (Method 1) 97.0% (AUC),t_(R)=13.78 min.

Step 3: To a stirred suspension of triphenylphosphine salt 3 (8.76 g,19.0 mmol) in THF (60 mL) at −78° C. was added n-butyl lithium (7.8 mL,2.5M solution in hexanes, 19.5 mmol) and the reaction mixture was warmedto room temperature. After 30 min the reaction mixture was again cooledto −78° C., a solution of 3-iodobenzaldehyde (4.41 g, 19.0 mmol) in THF(15 mL) was added, and the reaction mixture was warmed to roomtemperature. After 1 h, the reaction was quenched with saturated aqueousNH₄Cl (50 mL) and extracted with EtOAc. The combined organic layers wereconcentrated under reduced pressure and the resulting residue wasdissolved in MeOH (70 mL). The MeOH solution was partitioned betweenhexanes and water. The combined organics were washed with 70% MeOH-water(100 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by flash chromatography (100% hexanes) to givetrans-alkene 4 (2.12 g, 33%) as a white solid and cis-alkene 5 (1.15 g,18%) as a colorless oil. 4: ¹H NMR (500 MHz, CDCl₃) δ 7.84 (s, 1H), 7.59(d, J=7.7 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.06-7.10 (m, 5H), 6.49 (d,J=16.6 Hz, 1H), 2.35 (s, 6H). 5: ¹H NMR (500 MHz, CDCl₃) δ 7.44 (d,J=7.8 Hz, 1H), 7.37 (s, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.04 (d, J=7.6 Hz,2H), 6.88 (d, J⁼7.9 Hz, 1H), 6.81 (t, J=7.8 Hz, 1H), 6.59 (d, J=12.2 Hz,1H), 6.53 (d, J=12.2 Hz, 1H), 2.14 (s, 6H).

Step 4: To a stirred solution of trans-alkene 4 (1.86 g, 5.60 mmol) inDMF (5 mL) was added NaHCO₃ (1.49 g, 17.7 mmol), tetrabutylammoniumchloride (1.58 g, 5.70 mmol), and allyl alcohol (0.683 g, 11.8 mmol).The reaction flask was purged with nitrogen for 10 min then Pd(OAc)₂(0.029 g, 0.130 mmol) was added. After purging with nitrogen for anadditional 10 min the solution was stirred under nitrogen at roomtemperature. After 18 h the solution was diluted with EtOAc (50 mL) andthe resulting mixture was washed with water, 5% aqueous LiCl solution,and brine. The organics were dried over MgSO₄ and concentrated underreduced pressure to afford a dark oil. Purification by flashchromatography (0 to 20% EtOAc-hexanes gradient) provided aldehyde 6 asa colorless oil. Yield 1.05 g (71%): ¹H NMR (500 MHz, CDCl₃) δ 9.85 (t,J=1.1 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.29-7.32 (m, 2H), 7.07-7.12 (m,5H), 6.57 (d, J=16.6 Hz, 1H), 2.99 (t, J=7.6 Hz, 2H), 2.38-2.84 (m, 2H),2.37 (s, 6H).

Step 5: To a solution of aldehyde 6 (0.200 g, 0.76 mmol) in EtOH (15 mL)under nitrogen in a Parr flask was added 10% Pd/C (50% wet, 0.020 g).The flask was pressurized with hydrogen gas to 30 PSI and the mixturewas shaken for 1.5 h. The reaction mixture was filtered overdiatomaceous earth, the filter cake washed with EtOH (50 mL), and thefiltrate concentrated under reduced pressure to a yellow residue.Purification by flash chromatography (0 to 20% EtOAc-hexanes) affordedaldehyde 7 as a yellow oil. Yield (0.100 g, 50%): ¹H NMR (500 MHz,CDCl₃) δ 9.82 (t, J=1.4 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 7.00-7.06 (m, 5H), 2.88-2.95 (m, 4H), 2.71-2.78 (m, 4H), 2.32(s, 6H).

Step 6: To a stirred solution of aldehyde 7 (0.100 g, 0.38 mmol) in MeOH(5 mL) was added 7M NH₃ in MeOH (1 mL) and a small scoop of powderedmolecular sieves. The flask was stoppered and stirred for 1.5 h, atwhich time NaBH₄ (0.022 g, 0.58 mmol) was added. The solution wasstirred for an additional 3 h, filtered over diatomaceous earth, thefilter cake rinsed with MeOH (50 mL) and the filtrate concentrated underreduced pressure. Purification of the resulting residue by flashchromatography (5% 7 M NH₃ in MeOH—CH₂Cl₂) gave3-(3-(2,6-dimethylphenethyl)phenyl)propan-1-amine as a free base. Yield(0.050 g, 50%). The free base was converted to the HCl salt by thefollowing procedure: To a stirred solution of3-(3-(2,6-dimethylphenethyl)phenyl)propan-1-amine (0.050 g, 0.17 mmol)in diethyl ether (2 mL) was added 1N HCl in ether (0.2 mL, 0.2 mmol).After stirring for 1 h, the solid was collected by filtration and driedunder vacuum to give Example 1 hydrochloride as a white solid. Yield(0.022 g, 42%): mp 106-108° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.22 (d, J=7.5Hz, 1H), 7.06 (d, J=7.4 Hz, 2H), 6.99-6.96 (m, 4H), 2.89-2.92 (m, 4H),2.72-2.75 (m, 2H), 2.67 (t, J=7.5 Hz, 2H), 2.26 (s, 6H), 1.93 (t, J=7.7Hz, 2H); ¹³C NMR (75 MHz, CD₃OD) δ 143.8, 141.7, 139.3, 127.1, 129.7,129.6, 129.1, 127.6, 127.0, 126.9; ESI MS m/z 268 [M+H]⁺; HPLC(Method 1) 98.9% (AUC), t_(R)=11.77 min. HRMS calcd for C₁₉H₂₅N [M+H]:268.2065. Found: 268.2064.

Example 2 Preparation of 1-(3-(3-aminopropyl)phenyl)-3-ethylpentan-3-ol

1-(3-(3-Aminopropyl)phenyl)-3-ethylpentan-3-ol was prepared followingthe method shown in scheme 2:

Step 1: To a stirred solution of 3-(3-bromophenyl)propanoic acid (8)(25.0 g, 109.1 mmole) in CH₂Cl₂ (150 ml) was added oxalyl chloride (27.7g, 218.3 mmol) followed by DMF (2 drops). The solution was stirred atroom temperature overnight. The mixture was concentrated under reducedpressure to give the crude acid chloride which was used immediately inthe next reaction.

Step 2: The crude acid chloride was dissolved in anhydrous THF (150 ml)and cooled in an ice bath. Ammonia gas was bubbled into the solution for3-4 minutes and the mixture was warmed to room temperature and stirredovernight. The mixture was concentrated under reduced pressure and theresidue was partitioned between saturated aqueous NaHCO₃ and EtOAc. Thecombined organics were dried over Na₂SO₄ and concentrated under reducedpressure to give amide 9 as a white solid. Yield (23.9 g, 96%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 7.35 (dt, J=6.4, 2.4 Hz, 1H), 7.26(br s, 1H), 7.18-7.24 (m, 2H), 6.75 (br s, 1H), 2.78 (t, J=7.6 Hz, 2H),2.34 (t, J=7.6 Hz, 2H).

Step 3: To an ice-cold, stirred solution of amide 9 (23.85 g, 104.6mmole) in THF (250 ml) was added BH₃-THF (209 ml of a 1.0 M solution inTHF, 209 mmol). The solution was warmed to room temperature and stirredfor 18 h. The reaction was quenched by the slow addition of 6N HCl untilpH 1 was achieved. The solution was stirred at room temperature for 4 hthen the pH was adjusted to >10 with the addition of 50% aqueous NaOH.The solution was extracted with EtOAc and the combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to give crude 3-(3-bromophenyl)propan-1-amine which was usedimmediately in the next reaction.

Step 4: Crude 3-(3-bromophenyl)propan-1-amine (ca. 104.6 mmol) wasstirred with ethyl trifluoroacetate (30 ml) overnight. The mixture wasconcentrated under reduced pressure. Purification by flashchromatography (20% EtOAc-hexanes) gave trifluoroacetamide 10. Yield(21.1 g, 62%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (br s, 1H), 7.43 (s,1H), 7.36 (dt, J=7.2, 2.0 Hz, 1H), 7.19-7.25 (m, 2H), 3.16 (q, J=6.8 Hz,2H), 2.57 (t, J=7.6 Hz, 2H), 1.77 (quint, J=7.2 Hz, 2H).

Step 5: To a degassed solution ofN-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide (10) (0.930 g, 3mmol) and 3-ethylpent-1-yn-3-ol (11) (0.670 g, 6 mmol) in triethylamine(4 mL) and DMF (12 mL) was added PdCl₂(PPh₃)₂ (0.053 g, 0.075 mmol),P(o-Tol)₃ (0.046 g, 0.15 mmol), and CuI (0.014 g, 0.075 mmol). Theresulting mixture was degassed and stirred under argon at 90° C. for 6h. The mixture was cooled to room temperature then concentrated underreduced pressure and diluted with EtOAc (100 mL) and water (70 mL).After vigorous shaking, the layers were separated. The organic layer wastreated with charcoal, dried over MgSO₄, filtered, and evaporated underreduced pressure. Purification by flash chromatography (7 to 60%EtOAc-hexanes gradient) gaveN-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide(12) as a yellow oil. Yield (0.663 g, 65%): ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (s, 1H), 7.17-7.28 (m, 4H), 3.16 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.2Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.53-1.67 (m, 4H), 0.97 (t, J=7.2Hz, 6H).

Step 6:N-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide(12) (0.660 g, 1.93 mmol) was dissolved in MeOH (15 mL), and an aqueoussolution of K₂CO₃ (0.42 g/3 mL) was added. The resulting mixture wasstirred at 45° C. for 4 h. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure thenpartitioned between EtOAc (50 mL) and water (50 mL). The combinedorganics were dried over Na₂SO₄, and concentrated under reducedpressure. Purification by flash chromatography (80 to 100% (9:1 EtOAc:7M NH₃ in MeOH):hexanes gradient) gave1-(3-(3-aminopropyl)phenyl)-3-ethylpent-1-yn-3-ol (13) as a light yellowoil. Yield (0.421 g, 89%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15-7.26 (m,4H), 5.11 (s, 1H), 2.56 (t, J=7.6 Hz, 2H), 2.47 (t, J=5.2 Hz, 2H),1.55-1.65 (m, 6H), 1.39 (br s, 2H), 0.97 (t, J=7.6 Hz, 6H).

Step 7: A degassed solution of1-(3-(3-aminopropyl)phenyl)-3-ethylpent-1-yn-3-ol (13, 0.130 g, 0.53mmol) in EtOH was stirred with a catalytic amount of 10% Pd/C underhydrogen atmosphere (atmospheric pressure) for 16 h. Filtration througha 0.45 μm membrane filter and concentration under reduced pressure gaveExample 2 as a clear oil. Yield (0.120 g, 91%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13 (t, J=7.6 Hz, 1H), 6.93-6.99 (m, 3H), 3.91 (br s, 1H),2.45-2.56 (m, 6H), 1.50-1.62 (m, 4H), 1.40 (br s, 2H), 1.38 (q, J=7.6Hz, 4H), 0.79 (t, J=7.6 Hz, 6H).

Example 3 Preparation of 4-(3-(3-aminopropyl)phenethyl)heptan-4-ol

4-(3-(3-Aminopropyl)phenethyl)heptan-4-ol was prepared following themethod used in Example 2.

Step 1: To a degassed solution ofN-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide (10) (2.29 g, 7.4mmol) and 4-ethynylheptan-4-ol (2.4 g, 18.5 mmol) in triethylamine (2mL) and DMF (18 mL) was added PdCl₂(PPh₃)₂ (0.130 g, 0.185 mmol),P(o-Tol)₃ (0.113 g, 0.37 mmol), and CuI (0.070 g, 0.37 mmol). Theresulting mixture was degassed and stirred under argon at 90° C.overnight. The mixture was cooled to room temperature and the solidswere removed by filtration through Celite. The filtrate was partitionedbetween diethyl ether and water and the combined organics were washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure.Purification by flash chromatography (6 to 50% EtOAc-hexanes gradient)gaveN-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide(12) as an amber oil. Yield (2.6 g, 95%): ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (s, 1H), 7.18-7.29 (m, 4H), 3.16 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.2Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.53-1.67 (m, 8H), 0.97 (t, J=7.2Hz, 6H).

Step 2: To a solution of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propyl)acetamide(2.6 g, 7.0 mmol) in MeOH (50 mL) was added concentrated aqueous NH₄OH(ca. 25 mL) and the solution was stirred at room temperature overnight.More concentrated aqueous NH₄OH (5 mL) was added and the mixture wasstirred overnight. The volatiles were removed by concentration underreduced pressure and the residue was extracted twice with EtOAc. Theorganic solution was washed with water and brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by flashchromatography (0 to 20% (20% 7M NH₃ in MeOH-EtOAc)-EtOAc gradient) gave4-((3-(3-aminopropyl)phenyl)ethynyl)heptan-4-ol as a clear oil. Yield(1.58 g, 83%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.26 (m, 4H), 5.12 (s,1H), 2.56 (t, J=7.2 Hz, 2H), 2.47 (t obs, J=7.2 Hz, 2H), 1.42-1.63 (m,12H), 0.90 (t, J=7.2 Hz, 6H).

Step 3: Hydrogenation of 4-(3-(3-aminopropyl)styryl)heptan-4-olfollowing the method used in Example 2, except that the reaction was runover 2 h, gave Example 3 as a clear oil. Yield (0.2516 g, 50%): ¹H NMR(400 MHz, CD₃OD) δ 7.15 (t, J=7.2 Hz, 1H), 6.98-7.02 (m, 3H), 2.55-2.67(m, 6H), 1.77 (quint, J=7.6 Hz, 2H), 1.67 (dt, J=8.0, 4.4 Hz, 2H),1.43-1.49 (m, 4H), 1.31-1.42 (m, 4H), 0.93 (t, J=7.2, 6H).

Example 4 Preparation of 4-(3-(3-aminopropyl)phenyl)-2-methylbutan-2-ol

4-(3-(3-Aminopropyl)phenyl)-2-methylbutan-2-ol was prepared followingthe method used in Example 2.

Step 1: Coupling of 2-methylbut-3-yn-2-ol with bromide 10 in THF at 70°C. without the use of tri-o-tolylphosphine gave2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-methylbut-1-ynyl)phenyl)propyl)acetamide.Yield (0.5 g, 81%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (br s, 1H),7.17-7.28 (m, 4H), 3.16 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.76(quint, J=7.6 Hz, 2H), 1.44 (s, 3H), 1.35 (s, 3H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-methylbut-1-ynyl)phenyl)propyl)acetamidegave 4-(3-(3-aminopropyl)phenyl)-2-methylbut-3-yn-2-ol. The product waspurified by flash chromatography (80% to 100% (10% 7 N NH₃-MeOH inEtOAc)-hexanes gradient) to give a light yellow oil. Yield (0.212 g,62%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.26 (m, 4H), 5.41 (br s, 1H),2.56 (t, J=7.2 Hz, 2H), 2.47-2.50 (m, 2H), 1.55-1.63 (m, 2H), 1.44 (s,6H), 1.36 (br s, 2H).

Step 3: Hydrogenation of4-(3-(3-aminopropyl)phenyl)-2-methylbut-3-yn-2-ol following the methodused Example 2, except that the reaction was run for 3.5 h, gave Example4. Yield (0.0488 g, 80%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (t, J=7.6 Hz,1H), 6.96-6.99 (m, 3H), 4.19 (br s, 1H), 2.45-2.57 (m, 6H), 1.55-1.62(m, 4H), 1.48 (br s, 2H), 1.12 (s, 6H).

Example 5 Preparation of 3-(3-(3-methoxypropyl)phenyl)propan-1-amine

3-(3-(3-Methoxypropyl)phenyl)propan-1-amine was prepared following themethod used in Example 4.

Step 1: Coupling of 3-methoxyprop-1-yne with bromide 10 gave2,2,2-trifluoro-N-(3-(3-(3-methoxyprop-1-ynyl)phenyl)-propyl)acetamideas a light yellow oil. Yield (0.193 g, 32%): ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (br s, 1H), 7.21-7.31 (m, 4H), 4.30 (s, 2H), 3.31 (s, 3H), 3.16 (q,J=7.2 Hz, 2H), 2.56 (t, J=7.6 Hz, 2H), 1.77 (quint, J=7.2 Hz, 2H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-methoxyprop-1-ynyl)phenyl)propyl)acetamidegave 3-(3-(3-methoxyprop-1-ynyl)phenyl)propan-1-amine as a clear oil.Yield (0.069 g, 54%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.19-7.28 (m, 4H),4.29 (s, 2H), 3.31 (s, 3H), 2.57 (t, J=7.6 Hz, 2H), 2.48-2.51 (m, 2H),1.56-1.63 (m, 2H), 1.36 (br s, 2H).

Step 3: Hydrogenation of 3-(3-(4-methoxybut-1-ynyl)phenyl)propan-1-aminefollowing the method used to prepare Example 4 gave Example 5. Yield(0.018 g): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15 (t, J=7.6 Hz, 1H), 6.94-6.99(m, 3H), 3.28 (t, J=6.4 Hz, 2H), 3.21 (s, 3H), 2.45-2.57 (m, 6H),1.71-1.78 (m, 2H), 1.59 (quint, J=7.2 Hz, 2H), 1.50 (br s, 2H).

Example 6 Preparation of 3-(3-(3-aminopropyl)phenyl)propan-1-ol

3-(3-(3-Aminopropyl)phenyl)propan-1-ol was prepared following the methodused in Example 4.

Step 1: Coupling of prop-2-yn-1-ol with bromide 10 gave2,2,2-trifluoro-N-(3-(3-(3-hydroxyprop-1-ynyl)phenyl)propyl)acetamide asa light yellow oil. Yield (0.148 g, 26%): ¹H NMR (400 MHz, DMSO-d₆) δ9.41 (br s, 1H), 7.19-7.29 (m, 4H), 5.28 (t, J=5.6 Hz, 1H), 4.27 (d,J=6.4 Hz, 2H), 3.16 (t, J=7.2 Hz, 2H), 2.56 (t, J=7.6 Hz, 2H), 1.76 (q,J=7.6 Hz, 2H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxyprop-1-ynyl)phenyl)propyl)acetamidegave 3-(3-(3-aminopropyl)phenyl)prop-2-yn-1-ol as a clear oil. Yield(0.073 g, 76%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.17-7.27 (m, 4H), 5.28 (brs, 1H), 4.27 (d, J=3.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 2.47-2.49 (m,2H), 1.52-1.63 (m, 4H).

Step 3: Hydrogenation of 3-(3-(3-aminopropyl)phenyl)prop-2-yn-1-olfollowing the method used to prepare Example 4 gave Example 6 as a clearoil. Yield (0.018 g): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (t, J=7.6 Hz,1H), 6.94-6.99 (m, 3H), 4.41 (br s, 1H), 3.38 (t, J=6.4 Hz, 2H),2.45-2.56 (m, 6H), 1.55-1.70 (m, 6H).

Example 7 Preparation of 1-(3-(3-aminopropyl)phenethyl)cyclohexanol

1-(3-(3-Aminopropyl)phenethyl)cyclohexanol was prepared following themethod used in Example 4 except that hydrogenation was conducted beforedeprotection of the amine.

Step 1: To a solution of bromide 10 (2.0 g, 6.45 mmol) and1-ethynylcyclohexanol (1.2 g, 9.67 mmol) in triethylamine (40 mL) wasadded CuI (0.0246 g, 0.129 mmol). The mixture was degassed with argonfor 2-3 min, then PdCl₂(PPh₃)₂ (0.0905 g, 0.129 mmol) was added. Thereaction mixture was degassed with argon again then stirred at 70° C.overnight under argon. After cooling to room temperature, the mixturewas concentrated under reduced pressure and suspended in EtOAc-hexanes(50%, 50 mL). Solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. Purification by flashchromatography gave2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamideas a clear oil. Yield (1.74 g, 76%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40(br s, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.17-7.24 (m, 3H), 5.37 (s, 1H),3.16 (q, J=6.8 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.15-1.83 (m, 12H).

Step 2: A solution of2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide(0.51 g, 1.44 mmol) in MeOH (15 mL) was degassed with argon for 2 min.To this solution was added 10% Pd/C (0.075 g) and the mixture was placedunder H₂ at 40 PSI on a Parr shaker overnight. Solids were removed byfiltration and the filtrate was concentrated under reduced pressure togive the crude product as a clear oil. This compound was used in thenext synthetic step without purification. Yield (0.509 g, 99%): ¹H NMR(400 MHz, DMSO-d₆) δ 9.40 (br s, 1H), 7.14 (t, J=7.6 Hz, 1H), 6.95-7.00(m, 3H), 3.96 (s, 1H), 3.18 (q, J=6.8 Hz, 2H), 2.51-2.57 (m, 4H),1.72-1.79 (m, 2H), 1.15-1.59 (m, 12H).

Step 3:2,2,2-Trifluoro-N-(3-(3-((1-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamidewas deprotected following the method used in Example 2 except that 5equivalents of K₂CO₃ were used and the reaction mixture was heated at55° C. for 3 h. Purification by flash chromatography (10% 7M NH₃ inMeOH—CH₂Cl₂) gave Example 7 as a white solid. Yield (0.840 g, 96%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.13 (t, J=7.2 Hz, 1H), 6.93-6.99 (m, 3H), 3.96(br s, 1H), 2.49-2.57 (m, 4H), 1.16-1.63 (m, 18H).

Example 8 Preparation of 1-(3-(3-aminopropyl)phenyl)hexan-3-ol

1-(3-(3-Aminopropyl)phenyl)hexan-3-ol was prepared following the methodused in Example 4.

Step 1: Coupling of hex-1-yn-3-ol with bromide 10 gave2,2,2-trifluoro-N-(3-(3-(3-hydroxyhex-1-ynyl)phenyl)propyl)acetamide asa brown oil. Yield (0.271 g, 41%).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxyhex-1-ynyl)phenyl)propyl)acetamidegave 1-(3-(3-aminopropyl)phenyl)hex-1-yn-3-ol. Yield (0.086 g, 45%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.16-7.26 (m, 4H), 5.36 (t, J=5.2 Hz, 1H), 4.41(dt, J=6.4, 5.2 Hz, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.47-2.49 (m, 2H),1.38-1.64 (m, 8H), 0.90 (t, J=7.2 Hz, 3H).

Step 3: Hydrogenation of 1-(3-(3-aminopropyl)phenyl)hex-1-yn-3-olfollowing the method used to prepare Example 4 gave Example 8. Yield(0.0296 g): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (t, J=7.6 Hz, 1H),6.92-6.99 (m, 3H), 4.33 (d, J=5.2 Hz, 1H), 3.89 (m, 1H), 2.45-2.67 (m,6H), 1.23-1.62 (m, 10H), 0.83 (t, J=7.2 Hz, 3H).

Example 9 Preparation of 4-(3-(2-aminoethoxy)phenethyl)heptan-4-ol

4-(3-(2-Aminoethoxy)phenethyl)heptan-4-ol was prepared following themethod shown in scheme 3:

Step 1: To a solution of 3-bromophenol (14) (36.38 g, 210.3 mmol) inacetone (175 ml) was added K₂CO₃ (0.033 g, 237 mmol) and 2-bromoethanol(20 ml, 283.3 mmol). The reaction mixture was heated at reflux underargon for 4 days. After cooling to room temperature, the mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was dissolved in diethyl ether (150 ml) and the solution waswashed successively with water, 10% aqueous NaOH, 5% aqueous NaOH,water, and brine. The solution was dried over MgSO₄ and concentratedunder reduced pressure to give 2-(3-bromophenoxy)ethanol (15) as a lightbrown oil. Yield (21.07 g, 46%): ¹H NMR (400 MHz, CDCl₃) δ 7.14 (t,J=7.8 Hz, 1H), 7.07-7.12 (m, 2H), 6.85 (ddd, J=7.8, 2.4, 1.3 Hz, 1H),4.06 (m, 2H), 3.95 (m, 2H), 2.11 (t, J=12.3 Hz. 1H).

Step 2: To an ice cold mixture of 2-(3-bromophenoxy)ethanol (15) (16.06g, 74.0 mmol) and triethylamine (9.12 g, 90.13 ml) in anhydrous CH₂Cl₂(120 ml) under argon was slowly added neat methanesulfonyl chloride (6ml, 77.2 mmol). The reaction mixture was stirred at 0° C. for 15 min.The mixture was concentrated under reduced pressure and the residue waspartitioned between EtOAc and water. The combined organics were washedwith water and brine, dried over MgSO₄, and concentrated under reducedpressure to give 2-(3-bromophenoxy)ethyl methanesulfonate (16) as abrownish oil. This product was used without further purification in thenext reaction. Yield (21.32 g, 98%): ¹H NMR (400 MHz, CDCl₃) δ 7.16 (t,J=7.8 Hz, 1H), 7.11-7.14 (m, 1H), 7.07 (m, 1H), 6.39 (ddd, J=7.6, 2.5,1.8 Hz, 1H), 4.56 (m, 2H), 4.22 (m, 2H), 3.08 (s, 3H).

Step 3: To a solution of mesylate 16 (24.05 g, 81.5 mmol) in anhydrousDMF (160 ml) was added potassium phthalimide (15.53 g, 83.8 mmol) andthe reaction mixture was stirred at 60° C. for 14 h. The mixture wasconcentrated under reduced pressure and the residue was partitionedbetween hexane-EtOAc (7:1) and water. A precipitate formed which wascollected by filtration, washed excessively with water and hexane, thendried in vacuum to give N-(2-(3-Bromophenoxy)ethyl)phthalimide (17) aswhite fluffy crystals (22.05 g). To collect a second batch of crystals,the organic layer of the filtrate was concentrated under reducedpressure. The residue was suspended in 10% EtOAc-hexanes. The solutionwas washed with water and the precipitate collected by filtration,washed excessively with water, then hexane and dried in vacuum to givephthalimide 17 (5.65 g). Combined yield (21.18 g, 98%). ¹H NMR (400 MHz,CDCl₃) δ 7.86 (m, 2H), 7.73 (m, 2H), 7.03-7.12 (m, 3H), 6.80 (ddd,J=8.0, 2.5, 1.4 Hz, 1H), 4.21 (t, J=6.9 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H).

Step 4: To a suspension of phthalimide 17 (22.82 g, 65.9 mmol) inabsolute EtOH (200 ml) was added hydrazine hydrate (6 ml, 123.7 mmol)and reaction mixture was heated at reflux under argon for 1.5 h. Aftercooling to room temperature, the mixture was filtered and the filtratewas concentrated under reduced pressure. The residue was re-suspended inhexane (100 ml) and solids were removed by filtration. The filtrate wasconcentrated under reduced pressure. The residue was then taken up inEtOH and concentrated under reduced pressure. This procedure wasrepeated with toluene to give amine 18 as a thick yellow oil. Yield(10.63 g, 75%): ¹H NMR (400 MHz, CDCl₃) δ 7.06-7.15 (m, 3H), 6.84 (ddd,J=8.0, 2.5, 1.2 Hz, 1H), 3.96 (t, J=5.3 Hz, 2H), 3.07 (t, J=5.09 Hz,2H), 1.43 (s, 2H).

Step 5: To a solution of amine 18 (10.63 g, 49.2 mmol) in anhydrous THF(80 ml) was added ethyl trifluoroacetate (12 ml, 100.6 mmol) and thereaction mixture was stirred at room temperature overnight. The solutionwas concentrated under reduced pressure and the residue was dissolved in50% EtOAc-hexanes. The solution was filtered through a layer of a silicagel and eluted with 50% EtOAc-hexanes. Concentration under reducedpressure gave bromide 19 as pale yellow oil which crystallized uponstanding to a pale yellow solid. Yield (13.69 g, 89%): ¹H NMR (400 MHz,CDCl₃) δ 7.16 (t, J=8.0 Hz, 1H), 7.12-7.14 (m, 1H), 7.05-7.07 (m, 1H),6.83 (ddd, J=7.6, 2.5, 1.8 Hz, 1H), 6.75 (br s, 1H), 4.09 (t, J=4.9 Hz,2H), 3.78 (dt, J=5.5 Hz, 2H).

Step 6: Bromide 19 was coupled with alkynol 20 following the proceduredescribed in Example 2 except that the reaction was run for 20 h, togive alkyne 21 as a yellow oil. Yield (0.89 g, 73%): ¹H NMR (400 MHz,CDCl₃) δ 7.22 (t, J=8.0 Hz, 1H), 7.06 (dt, J=7.6, 1.0 Hz, 1H), 6.93 (dd,J=2.5, 1.4 Hz, 1H), 6.85 (ddd, J=8.4, 2.7, 1.0 Hz, 1H), 6.77 (br s, 1H),4.09 (t, J=5.1 Hz, 2H), 3.78 (dt, J=5.5 Hz, 2H), 2.00 (s, 1H), 1.67-1.73(m, 4H), 1.57-1.61 (m, 4H), 0.98 (t, J=7.4 Hz, 6H).

Step 7: Alkyne 21 was deprotected according to the procedure describedin Example 2 except that the reaction was run with 5 equivalents ofK₂CO₃ at room temperature for 7 h, followed by purification by flashchromatography (eluent 90% EtOAc: (7M NH₃ in MeOH) to give amine 22trifluoroacetate as a cream-colored solid. Yield (5 g, 76%). ¹H NMR (400MHz, DMSO-d₆) δ 7.23 (t, J=7.8 Hz, 1H), 6.92-6.93 (m, 1H), 6.90-6.91 (m,1H), 6.85-6.86 (m, 1H), 5.13 (br s, 1H), 3.89 (t, J=5.9 Hz, 2H), 2.83(t, J=5.7 Hz, 2H), 1.42-1.60 (m, 10H), 0.89 (t, J=7.2 Hz, 6H); ¹³C NMR(100 MHz, DMSO-d6) δ 159.28, 130.47, 124.49, 124.26, 117,34, 115.80,94.78, 83,15, 71.03, 70.26, 44.86, 41.60, 17.96, 15.01. ESI MS m/z276.39 [M+H]⁺, 258.38 [M+H−H₂O]⁺.

Step 8: Hydrogenation of amine 22 was conducted following the methodused to prepare Example 2. A solution of the crude product in 10%MeOH—CH₂Cl₂ (5 mL) was filtered through Celite/silica/sand. The solidsin the funnel were rinsed with more 10% MeOH—CH₂Cl₂, then the filtratewas concentrated under reduced pressure to give Example 9 as a colorlessoil. Yield (0.201 g, 80%): ¹H NMR (400 MHz, CDCl₃) δ 7.18 (t, J=8.0 Hz,1H), 6.72-6.80 (m, 3H), 3.98 (t, J=5.2 Hz, 2H), 3.07 (t, J=5.2 Hz, 2H),2.58-2.62 (m, 2H), 1.70-1.75 (m, 2H), 1.45-1.50 (m, 7H), 1.32-1.37 (m,4H), 0.94 (t, J=6.8 Hz, 6H).

Example 10 Preparation of 1-(3-(2-aminoethoxy)phenethyl)cycloheptanol

1-(3-(2-Aminoethoxy)phenethyl)cycloheptanol was prepared following themethod used in Example 9:

Step 1: Bromide 19 was coupled with 1-ethynylcycloheptanol following theprocedure described in Example 2 except that 1.5 equivalents of alkyneand triethylamine were used and the reaction was heated for 2 h. Afterthe reaction mixture was cooled to room temperature, it was partitionedbetween EtOAc and water then the combined organics were filtered throughCelite. The filtrate was dried over Na₂SO₄ and treated with activatedcharcoal.

Following filtration, the solution was concentrated under reducedpressure. Purification by flash chromatography (10 to 50% EtOAc-hexanesgradient) gave2,2,2-trifluoro-N-(2-(3-((1-hydroxycycloheptyl)ethynyl)phenoxy)ethyl)acetamideas an orange oil. Yield (1.078 g, 60%): ¹H NMR (400 MHz, CDCl₃) δ 7.2(br s, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.02 (dt, J=7.2, 0.8 Hz, 1H), 6.90(dd, J=2.4, 1.6 Hz, 1H), 6.81 (ddd, J=8.4, 2.4, 0.8 Hz, 1H), 4.05 (t,J=5.2 Hz, 2H), 3.72 (q, J=5.3 Hz, 2H), 2.43 (br s, 1H), 2.05-2.11 (m,2H), 1.84-1.91 (m, 2H), 1.53-1.70 (m, 8H).

Step 2: To a solution of2,2,2-trifluoro-N-(2-(3-((1-hydroxycycloheptyl)ethynyl)phenoxy)ethyl)acetamide(1.07 g, 2.9 mmol) in MeOH (20 mL) was added saturated aqueous K₂CO₃(ca. 10 mL). The reaction mixture was stirred vigorously and heated at50° C. for 2 h. After removal of the volatiles by concentration underreduced pressure, the mixture was partitioned into EtOAc and water. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. Purification by flash chromatography (10% 7M NH₃ inMeOH-EtOAc) gave 1-((3-(2-aminoethoxy)phenyl)ethynyl)cycloheptanol as apale yellow solid. (Yield 0.70 g, 88%): ¹H NMR (400 MHz, CDCl₃) δ 7.19(t, J=8.0 Hz, 1H), 7.01 (dt, J=8.0, 0.8 Hz, 1H), 6.95 (dd, J=2.8, 1.6Hz, 1H), 6.85 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 3.97 (t, J=4.8 Hz, 2H),3.07 (br s, 2H), 2.08-2.13 (m, 2H), 1.87-1.94 (m, 2H), 1.59-1.74 (m,11H).

Step 3: Hydrogenation of1-((3-(2-aminoethoxy)phenyl)ethynyl)cycloheptanol following the methodused to prepare example 2 gave Example 10 as a colorless oil. Yield(0.186 g, 52%): ¹H NMR (400 MHz, CDCl₃) δ 7.16 (t, J=8.0 Hz, 1H),6.75-6.79 (m, 2H), 6.70 (dd, J=8.0, 2.0 Hz, 1H), 3.96 (t, J=5.2 Hz, 2H),3.04 (t, J=4.8 Hz, 2H), 2.63-2.67 (m, 2H), 2.10 (br s, 2H), 1.72-1.76(m, 2H), 1.67-1.69 (m, 4H), 1.36-1.65 (m, 8H).

Example 11 Preparation of4-(3-(2-aminoethoxy)phenethyl)tetrahydro-2H-thiopyran-4-ol

4-(3-(2-Aminoethoxy)phenethyl)tetrahydro-2H-thiopyran-4-ol was preparedfollowing the method used in Examples 2 and 9.

Step 1: Coupling of 4-ethynyltetrahydro-2H-thiopyran-4-ol with bromide19 was conducted following the method used in Example 2 except that thereaction was run in THF at 60° C. overnight. Purification by flashchromatography (1:2 EtOAc:heptane) gave2,2,2-trifluoro-N-(3-(3-((4-hydroxytetrahydro-2H-thiopyran-4-yl)ethynyl)phenyl)propyl)acetamideas a pale yellow oil. Yield (0.822 g, 72%): ¹H NMR (400 MHz, CDCl₃) δ7.26 (t, J=4.5 Hz, 1H), 7.07 (dt, J=7.6, 1.2 Hz, 1H), 6.95 (dd, J=2.5,1.4 Hz, 1H), 6.87 (ddd, J=8.2, 2.5, 0.8 Hz, 1H), 4.10 (m, 2H), 3.79 (q,J=5.5 Hz, 2H), 2.73-2.92 (m, 4H), 2.26-2.31 (m, 2H), 2.01-2.04 (m, 2H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-((4-hydroxytetrahydro-2H-thiopyran-4-yl)ethynyl)phenyl)propyl)acetamidewas conducted following the method used for the preparation of Example 9except that 2 equivalents of K₂CO₃ were used and the reaction was heatedat 50° C. for 2 h. After cooling to room temperature, the reactionmixture was partitioned between EtOAc and water. The combined organicswere washed with water and brine, dried over Na₂SO₄ and concentratedunder reduced pressure. Purification by flash chromatography(CH₂Cl₂/EtOH/NH₄OH 85:14:1) gave4-((3-(2-aminoethoxy)phenyl)ethynyl)tetrahydro-2H-thiopyran-4-ol as awhite amorphous solid. Yield (0.41 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ7.23-7.28 (m, 1H), 6.93-6.98 (m, 3H), 5.69 (br s, 1H), 3.90 (t, J=5.8Hz, 2H), 2.83 (t, J=5.8 Hz, 2H), 2.69 (t, J=5.6 Hz, 4H), 2.09 (dt,J=13.0, 4.6 Hz, 2H), 1.80 (quint, J=6.6 Hz, 2H), 1.60 (br s, 2H).

Step 3: Hydrogenation of4-((3-(2-aminoethoxy)phenyl)ethynyl)tetrahydro-2H-thiopyran-4-ol wasconducted following the method used to prepare Example 2 except thatEtOAc-MeOH (90%) was used as the reaction solvent. Example 11 wasisolated as a colorless oil. Yield (0.179 g, 98%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13 (t, J=8 Hz, 1H), 6.34-6.88 (m, 3H), 4.26 (br s, 1H),3.86 (t, J=6.0 Hz, 2H), 2.57-2.88 (m, 4H), 2.53-2.56 (m, 2H), 2.32-2.37(m, 2H), 1.73-1.78 (m, 2H), 1.42-1.62 (m, 6H).

Example 12 Preparation of 1-(3-(2-aminoethoxy)phenethyl)cyclohexanol

1-(3-(2-Aminoethoxy)phenethyl)cyclohexanol was prepared following themethod shown in Scheme 4:

Step 1: To an ice cold solution of 3-bromophenol (14) (2.0 g, 11.56mmol), N-(2-hydroxyethyl)phthalimide (2.21 g, 11.6 mmol) and triphenylphosphine (3.03 g, 11.6 mmol) in anhydrous THF (25 mL) was added diethylazodicarboxylate (2.57 g, 12.7 mmol) slowly. The reaction mixture wasallowed to warm to room temperature and stirred overnight. Afterconcentration under reduced pressure, 50% EtOAc-hexanes (100 mL) wasadded and the mixture was warmed to 60° C. After cooling to roomtemperature, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. Purification by flashchromatography (10% EtOAc-hexanes) gave bromide 17 as a white solid.Yield (1.92 g, 48%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.82-7.88 (m, 4H), 7.19(t, J=8.4 Hz, 1H), 7.06-7.09 (m, 2H), 6.87-6.90 (m, 1H), 4.22 (t, J=5.6Hz, 2H), 3.93 (t, J=5.6 Hz, 2H).

Step 2: Coupling of bromide 17 with 1-ethynylcyclohexanol following themethod used in Example 7 followed by purification by flashchromatography (20% EtOAc-hexanes) gave compound 24 as a pale yellowoil. Yield (1.22 g, 57%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.82-7.88 (m, 4H),7.21 (t, J=8.0 Hz, 1H), 6.92 (dt, J=8.0, 0.8 Hz, 1H), 6.84-6.88 (m, 2H),5.38 (br s, 1H), 4.20 (t, J=5.6 Hz, 2H), 3.95 (t, J=5.6 Hz, 2H),1.78-1.82 (m, 2H), 1.59-1.62 (m, 2H), 1.41-1.53 (m, 4H), 1.22-1.94 (m,1H).

Step 3: Hydrogenation of compound 24 following the method used inExample 7 gave alcohol 25. Yield (0.512 g, quant.): ¹H NMR (400 MHz,DMSO-d₆) δ 7.81-7.88 (m, 4H), 7.10 (t, J=7.6 Hz, 1H), 6.64-6.71 (m, 3H),4.16 (t, J=5.6 Hz, 2H), 3.93 (t, J=6.8 Hz, 2H), 3.30 (s, 1H), 2.47-2.53(m, 4H), 1.15-1.56 (m, 10H).

Step 4: Deprotection of alcohol 25 was conducted following the methodused in Example 9 except that 5 equivalents of hydrazine hydrate wereused and the reaction was heated at 70° C. for 4 h. After cooling toroom temperature, solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. Purification by flashchromatography (10% 7M NH₃ in MeOH—CH₂Cl₂) gave Example 12. Yield(0.341, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (t, J=8.0 Hz, 1H),6.73-6.75 (m, 3H), 3.96 (br s, 1H), 3.86 (t, J=5.6 Hz, 2H), 2.83 (t,J=6.0 Hz, 2H), 2.52-2.56 (m, 2H), 1.16-1.60 (m, 12H).

Example 13 Preparation of 6-(3-(2-aminoethoxy)phenyl)hexan-1-ol

6-(3-(2-Aminoethoxy)phenyl)hexan-1-ol was prepared following the methodshown in scheme 5:

Step 1: To a solution of 3-bromophenol (14) (5.0 g, 28.9 mmol) in THF(100 mL) was added tert-butyl 2-hydroxyethylcarbamate (9.3 g, 161 mmol)and PPh₃ (30 g, 115 mmol). A solution of diisopropyl azodicarboxylate(22.6 mL, 115.6 mmol) in THF (40 mL) was added dropwise at roomtemperature. The reaction was stirred overnight at 50° C. After coolingto room temperature, the mixture was concentrated under reducedpressure. The residue was dissolved in EtOAc, washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure. Purification bycolumn chromatography (6% EtOAc-hexanes) provided bromide 26 as acolorless oil. Yield (8.34 g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 7.14 (t,J=8.0 Hz, 1H), 7.05-7.11 (m, 2H), 6.81-6.84 (m, 1H), 4.96 (br s, 1H),4.00 (t, J=5.2 Hz, 2H), 3.52 (q, J=4.8 Hz, 2H), 1.45 (s, 9H).

Step 2: To a degassed solution (bubbled with N₂) of bromide 26 (0.600 g,1.89 mmol) and alcohol 27 (0.241 mL, 2.27 mmol) in Et₃N (20 mL) wasadded PdCl₂(PPh₃)₂ (0.040 g, 0.056 mmol) and CuI (0.011 g, 0.056 mmol).The mixture was heated overnight at 70° C. After cooling to roomtemperature, the mixture was concentrated under reduced pressure,dissolved in EtOAc and filtered. The filtrate was washed with water andbrine, dried over Na₂SO₄ and concentrated under reduced pressure.Purification by flash chromatography (20% EtOAc-hexanes) provided alkyne28 as a brown oil. Yield (0.500 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 7.17(t, J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.91 (s, 1H), 6.81 (d, J=8.4Hz, 1H), 4.72 (br s, 1H), 4.00 (t, J=4.8 Hz, 2H), 3.72 (m, 2H),3.48-3.55 (m, 2H), 2.46 (d, J=6.8 Hz, 2H), 1.66-1.79 (m, 4H), 1.58 (s,1H), 1.45 (s, 9H).

Step 3: Alkyne 28 (500 mg, 1.52 mmol) was dissolved in HCl-dioxane (12mL of a saturated solution) and stirred overnight at room temperature.The mixture was concentrated under reduced pressure then purified byPrep HPLC using Method 2P to give amine 29 hydrochloride as a brownsolid. Yield (0.161 g, 40%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (br s,3H), 7.22-7.27 (m, 1H), 6.92-6.97 (m, 3H), 4.14 (t, J=5.0 Hz, 2H), 3.40(t, J=5.8 Hz, 2H), 3.14-3.15 (m, 2H), 2.39 (t, J=6.6 Hz, 2H), 1.51-1.53(m, 4H).

Step 4: To a stirred solution of amine 29 hydrochloride (0.100 g, 0.42mmol) in MeOH was added 5% Pd/C (30% w/w, 0.023 g) under nitrogen. Themixture was bubbled with hydrogen then stirred at 50° C. for 2 h underhydrogen. After cooling to room temperature, the solids were removed byfiltration through Celite. The filter cake was rinsed with additionalMeOH and the filtrate concentrated under reduced pressure. Example 13hydrochloride was isolated as a cream-colored solid. Yield (0.048 g,47%): ¹H NMR (400 MHz, CD₃OD) δ 7.18 (t, J=8.0 Hz, 1H), 6.78-6.83 (m,3H), 4.19 (t, J=5.2 Hz, 2H), 3.52 (t, J=6.6 Hz, 2H), 3.34 (t, J=5.2 Hz,2H), 2.59 (t, J=7.6 Hz, 2H), 1.58-1.63 (m, 2H), 1.43-1.52 (m, 2H),1.24-1.42 (m, 4H).

Example 14 Preparation of 2-(3-(3-cyclopentylpropyl)phenoxy)ethanamine

2-(3-(3-Cyclopentylpropyl)phenoxy)ethanamine was prepared following themethod used in Example 13.

Step 1: Coupling of prop-2-ynylcyclopentane with bromide 26 andpurification by flash chromatography (15% EtOAc-hexanes) gave tert-butyl2-(3-(3-cyclopentylprop-1-ynyl)phenoxy)ethylcarbamate as a white solid.Yield (0.500 g, 77%): ¹H NMR (400 MHz, CDCl₃) δ 6.91-7.21 (m, 3H),6.80-6.84 (m, 1H), 4.97 (br s, 1H), 4.00 (t, J=4.8 Hz, 2H), 3.52 (q,J=4.4 Hz, 2H), 2.40 (d, J=6.8 Hz, 2H), 2.07-2.17 (m, 1H), 1.80-1.87 (m,2H), 1.48-1.70 (m, 4H), 1.45 (s, 9H), 1.29-1.40 (m, 2H).

Step 2: Deprotection of tert-butyl2-(3-(3-cyclopentylprop-1-ynyl)phenoxy)ethylcarbamate with HCl indioxane gave 2-(3-(3-cyclopentylprop-1-ynyl)phenoxy)ethanamine as awhite solid. Yield (0.160 g, 45%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.20-7.24(m, 1H), 6.89-6.94 (m, 3H), 4.00 (t, J=5.0 Hz, 2H), 3.00 (br s, 2H),3.81 (d, J=6.8 Hz, 2H), 2.04 (quint, J=7.2, 1H), 1.71-1.78 (m, 2H),1.44-1.62 (m, 4H), 1.20-1.31 (m, 2H).

Step 3: Hydrogenation of2-(3-(3-cyclopentylprop-1-ynyl)phenoxy)ethanamine following the methodused to prepare Example 13 gave Example 14 trifluoroacetate as a whitesolid. Yield (0.063 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (br s,3H), 7.18 (t, J=8.0 Hz, 1H), 6.74-6.79 (m, 3H), 4.09 (t, J=5.2 Hz, 2H),3.18 (m, 2H), 2.42-2.53 (m, 2H), 1.62-1.73 (m, 3H), 1.38-1.58 (m, 6H),1.22-1.28 (m, 2H), 0.92-1.04 (m, 2H).

Example 15 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenethyl)cyclohexanol

1-(3-(3-Amino-1-hydroxypropyl)phenethyl)cyclohexanol was preparedfollowing the method shown in Scheme 6:

Step 1: 3-Bromobenzaldehyde was coupled with alkynol 23 following themethod used in Example 7 except that the reaction was heated for 2 h.After the reaction mixture was cooled to room temperature, it wasconcentrated under reduced pressure and partitioned between EtOAc andwater. The organics were dried over Na₂SO₄ and concentrated underreduced pressure. Purification by flash chromatography (30%EtOAc-hexanes) gave alkyne 31. Yield (3.52 g, 53%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.99 (s, 1H), 7.84-7.90 (m, 2H), 7.68-7.71 (m, 1H), 7.58 (t,J=7.6 Hz, 1H), 5.50 (s, 1H), 1.19-1.87 (m, 10H).

Step 2: Alkynol 31 was hydrogenated following the method used in Example2 except that EtOAc was used as the solvent and the reaction was run for3 h. Purification by flash chromatography (20% EtOAc-hexanes) gavealdehyde 32 as a colorless oil. Yield (2.82 g, 79%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.97 (s, 1H), 7.68-7.71 (m, 2H), 7.52-7.54 (m, 1H), 7.48 (t,J=7.6 Hz, 1H), 4.03 (s, 1H), 2.68-2.72 (m, 2H), 1.19-1.63 (m, 12H).

Step 3: To a −78° C. solution of LDA (13.3 mL of a 2M solution inheptane/THF/ethylbenzene, 26.51 mmol) in anhydrous THF (50 mL) was addedacetonitrile (1.33 mL, 25.31 mmol) slowly and the mixture was stirredfor 15 min. A solution of aldehyde 32 (2.8 g, 12.05 mmol) in THF (30 mL)was added via syringe. After warming slowly to room temperature, thereaction mixture was quenched with saturated aqueous NH₄Cl (30 mL). Themixture was partitioned between EtOAc and water, the organics were driedover Na₂SO₄, and the solution was concentrated under reduced pressure.Purification by flash chromatography (40% EtOAc-hexanes) gavecyanohydrin 33 as a pale yellow oil. Yield (2.21 g, 67%): ¹H NMR (400MHz, DMSO-d₆) δ 7.07-7.24 (m, 4H), 5.86 (d, J=4.0 Hz, 1H), 4.83 (q,J=6.0 Hz, 1H), 3.99 (br s, 1H), 2.74-2.88 (m, 2H), 2.57-2.62 (m, 2H),1.14-1.61 (m, 12H).

Step 4: To an ice cold solution of cyanohydrin 33 (2.2 g, 8.05 mmol) inanhydrous THF (50 mL) was added LiAlH₄ (10.0 mL of a 2M solution in THF,20 mmol) slowly via syringe. During the addition, precipitates wereformed and additional THF (100 mL) was added. The reaction mixture wasallowed to warm to room temperature slowly over 2 h then solidNa₂SO₄.10H₂O was added slowly until gas evolution ceased. Solids wereremoved by filtration then the filtrate was dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by flashchromatography (10% 7M NH₃ in MeOH—CH₂Cl₂) gave Example 15 as an oilthat solidified upon standing. Yield (1.15 g, 52%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.16 (d, J=7.6 Hz, 1H), 6.99-7.12 (m, 3H), 4.59-4.62 (m, 1H),3.98 (br s, 1H), 2.49-2.67 (m, 4H), 1.16-1.63 (m, 17H).

Example 16 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenethyl)cycloheptanol

1-(3-(3-Amino-1-hydroxypropyl)phenethyl)cycloheptanol was preparedfollowing the method shown in scheme 7:

Step 1: To a −50° C. solution of potassium t-butoxide (703 mL of a 1.0 Msolution in THF, 703 mmol) was added acetonitrile (27.73 g, 675.6 mmol)via syringe over 5 min. The mixture was stirred at −50° C. for 30 min,then a solution of 3-bromobenzaldehyde (22) (100 g, 540.5 mmol) in THF(50 mL) was added over 5 min. The mixture was stirred for 30 min, thenallowed to warm to 0° C. The reaction mixture was quenched withsaturated aqueous NH₄Cl (250 mL) and the layers were separated. Theorganics were washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to afford3-(3-bromophenyl)-3-hydroxypropanenitrile (34) as a pale yellow oil.This material was used in the next synthetic step without furtherpurification. Yield (117.6 g, 96%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (t,J=1.6 Hz, 1H), 7.46 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 7.40 (dd, J=7.6, 2.0Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 6.05 (d, J=4.8 Hz, 1H), 2.80-2.94 (m,2H).

Step 2: To a solution of nitrile 34 (2.15 g, 9.5 mmol),1-ethynylcycloheptanol (35) (2.62 g, 19 mmol), and P(t-Bu)₃ (0.95 mL ofa 1M solution in dioxane, 0.95 mmol) in diisopropylamine (6 mL) anddioxane (30 mL) was added PdCl₂(PPh₃)₂ (0.33 g, 0.47 mmol) and CuI(0.090 g, 0.47 mmol). The mixture was degassed (argon/vacuum) thenheated at 45° C. overnight. After cooling to room temperature, themixture was concentrated under reduced pressure. Purification by flashchromatography (1:2 to 1:1 EtOAc-hexanes) twice gave alkyne 36 as a paleyellow oil. Yield (2.35 g, 87%): ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.46 (m,4H), 4.99-5.04 (m, 1H), 3.66-3.74 (m, 1H), 2.72-2.78 (m, 2H), 1.56-2.13(m, 12H).

Step 3: Alkyne 36 was hydrogenated following the method used in Example2 except that EtOAc was used as the solvent and the reaction was stirredfor 1.5 h. The product, diol 37, was used without purification. Yield(1.26 g, 97%): ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.26 (m, 4H), 4.95 (t,J=6.4 Hz, 1H), 3.55-3.60 (m, 2H), 2.63-2.71 (m, 4H), 1.32-1.72 (m, 12H).

Step 4: Diol 37 was reduced following the method used in Example 15. Thereaction was quenched with NaOH (0.3 mL of a 50% w/w solution), thenfiltered and concentrated under reduced pressure. Purification by flashchromatography (10% MeOH—CH₂Cl₂ then 10 to 20% 7M NH₃ in MeOH/CH₂Cl₂)gave Example 16 as a colorless oil that solidified to a white solid uponstanding. Yield (ca. 0.149 g, 67%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (t,J=7.6 Hz, 1H), 7.12 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.99 (t, J=7.6 Hz,1H), 4.60 (dd, J=7.6, 5.6 Hz, 1H), 3.97 (br s, 1H), 3.25 (br s, 2H),2.56-2.66 (m, 4H), 1.26-1.64 (m, 16H).

Example 17 Preparation of3-amino-1-(3-(2-cyclopentylethyl)phenyl)propan-1-ol

3-Amino-1-(3-(2-cyclopentylethyl)phenyl)propan-1-ol was preparedfollowing the method shown in scheme 8:

Step 1: To a solution of 3-(3-bromophenyl)-3-hydroxypropanenitrile (34)(117.5 g, 519.8 mmol) in THF (300 mL) under argon was addedborane-dimethylsulfide complex (68 mL; 10.0 M in BH₃, 675.7 mmol) via anaddition funnel over 30 min. The reaction mixture was heated at refluxfor 2.5 h. After cooling to room temperature, the reaction was quenchedwith the addition of HCl-MeOH (350 mL of a 1.25 M solution) over 30 min.The mixture was concentrated under reduced pressure then water was addedand the mixture was adjusted to pH ˜12 with 50% aqueous NaOH solution.The aqueous mixture was extracted with CH₂Cl₂ and the combined organicswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was dissolved in 10% MeOH—CH₂Cl₂ and eluted through a pad ofsilica with 10% MeOH—CH₂Cl₂ then 10% 7 M NH₃ in MeOH/CH₂Cl₂ to giveamine 38. This material was used in subsequent synthetic steps withoutfurther purification. Yield (106 g, 87%): ¹H NMR (400 MHz, DMSO-d₆) δ7.49 (m, 1H), 7.37 (dt, J=7.2, 1.6 Hz, 1H), 7.23-7.31 (m, 2H), 4.66 (t,J=6.8 Hz, 1H), 2.61 (m, 2H), 1.61 (q, J=6.8 Hz, 2H).

Step 2: To a solution of amine 38 (5.628 g, 26.0 mmol) in CH₂Cl₂ (20 mL)was added Et₃N (5.43 mL, 39.0 mmol) and di-tert-butyl dicarbonate (8.52g, 39.0 mmol). The reaction mixture was stirred overnight at roomtemperature then concentrated under reduced pressure. The residue wasdissolved in EtOAc, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by flashchromatography (13% EtOAc-hexanes) provided tert-butyl3-(3-bromophenyl)-3-hydroxypropylcarbamate (39) as a thick brown oil.Yield (4.0 g, 48%): ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.39 (d,J=8.0 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 4.87 (brs, 1H), 4.71 (d, J=6.4 Hz, 1H), 3.64 (br s, 1H), 3.50-3.59 (m, 1H),3.12-3.19 (m, 1H), 1.77-1.87 (m, 2H), 1.46 (s, 9H).

Step 3: Coupling of ethynylcyclopentane (40) with tert-butyl3-(3-bromophenyl)-3-hydroxypropylcarbamate (39) following the methodused in the synthesis of Example 13 gave tert-butyl3-(3-(cyclopentylethynyl)phenyl)-3-hydroxypropylcarbamate (41) as abrown oil. Yield (0.386 g, 92%).

Step 4: Deprotection of tert-butyl3-(3-(cyclopentylethynyl)phenyl)-3-hydroxypropylcarbamate (41) followingthe method used in Example 13 and purification by preparative HPLC(Method 1P) gave compound 42 trifluoroacetate as a white solid. Yield(0.15 g, 74%): ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.31 (m, 4H), 4.85 (dd,J=7.6, 4.0 Hz, 1H), 3.11-3.17 (m, 2H), 2.69 (quint, J=7.2 Hz, 1H),1.56-2.02 (m, 10H).

Step 5: Compound 42 trifluoroacetate was hydrogenated by the method usedin Example 13 except that the reaction was run overnight at roomtemperature. Example 17 trifluoroacetate was isolated as a white stickysolid. Yield (0.094 g, 84%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.64 (br s,3H), 7.20 (t, J=7.6 Hz, 1H), 7.03-7.11 (m, 3H), 5.48 (br s, 1H), 4.61(t, J=5.6 Hz, 1H), 2.76-2.87 (m, 2H), 2.54 (t, J=8.0 Hz, 2H), 1.63-1.84(m, 5H), 1.38-1.58 (m, 6H), 1.02-1.14 (m, 2H).

Example 18 Preparation of3-amino-1-(3-(3-phenylpropyl)phenyl)propan-1-ol

3-Amino-1-(3-(3-phenylpropyl)phenyl)propan-1-ol was prepared followingthe method used in Example 17:

Step 1: Coupling of prop-2-ynylbenzene with bromide 39 gave tert-butyl3-hydroxy-3-(3-(3-phenylprop-1-ynyl)phenyl)propylcarbamate as a brownoil. Yield (0.404 g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.45 (m, 3H),7.32-7.36 (m, 3H), 7.20-7.29 (m, 3H), 4.87 (br s, 1H), 4.72 (br s, 1H),3.83 (s, 2H), 3.51-3.54 (m, 1H), 3.35 (br s, 1H), 3.12- 3.19 (m, 1H),1.81-1.84 (m, 2H), 1.45 (s, 9H).

Step 2: Deprotection of tert-butyl3-hydroxy-3-(3-(3-phenylprop-1-ynyl)phenyl)propylcarbamate followed bypurification by preparative HPLC (Method 1P) gave3-amino-1-(3-(3-phenylprop-1-ynyl)phenyl)propan-1-ol trifluoroacetate asa white solid. Yield (0.114 g, 27%): ¹H NMR (400 MHz, CDCl₃) δ 7.92 (brs, 2H), 7.26-7.37 (m, 5H), 7.16-7.23 (m, 4H), 4.79 (dd, J=8.4, 3.6 Hz,1H), 3.75 (s, 2H), 3.02-3.16 (m, 2H), 1.93-1.98 (m, 2H).

Step 3: 3-Amino-1-(3-(3-phenylprop-1-ynyl)phenyl)propan-1-oltrifluoroacetate was hydrogenated by the method used in Example 13,except that the reaction was conducted for 1 h at 50° C., to giveExample 18 trifluoroacetate as a white solid. Yield (33%): ¹H NMR (400MHz, DMSO-d₆) δ 7.76 (br s, 3H), 7.24-7.31 (m, 3H), 7.09-7.21 (m, 6H),5.52 (br s, 1H), 4.65 (t, J=5.6 Hz, 1H), 2.67-2.89 (m, 2H), 2.52-2.64(m, 4H), 1.78-1.91 (m, 4H).

Example 19 Preparation of4-(3-(3-amino-1-hydroxypropyl)phenethyl)heptan-4-ol

4-(3-(3-Amino-1-hydroxypropyl)phenethyl)heptan-4-ol was preparedfollowing the method shown in scheme 9:

Step 1: To a solution of amine 38 (1.70 g, 7.39 mmol) in EtOH (10 mL)was added ethyl trifluoroacetate (10 mL). The mixture was stirred for 4h then concentrated under reduced pressure. Purification by flashchromatography (20% EtOAc-hexanes) gave aryl bromide 43 as a clear oil.Yield (0.820 g, 34%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (s, 1H), 7.51 (t,J=2.0 Hz, 1H), 7.41 (dt, J=7.6, 2.0 Hz, 1H), 7.25-7.32 (m, 2H), 5.46 (d,J=6.4 Hz, 1H), 4.55-4.60 (m, 1H), 3.20-3.23 (m, 2H), 1.75-1.82 (m, 2H).

Step 2: Coupling of 4-ethynylheptan-4-ol (44) with bromide 43 wasconducted following the method used to prepare Example 7. Purificationby flash chromatography (40% EtOAc-hexanes) gave alkyne 45 as a clearoil. Yield (0.520 g, 54%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (m, 1H),7.29-7.34 (m, 3H), 7.22-7.26 (m, 1H), 5.39 (d, J=4.4 Hz, 1H), 5.12 (s,1H), 4.59 (dt, J=8.4, 4.8 Hz, 1H), 3.25 (quint, J=7.6 Hz, 2H), 1.80(quint, J=8.0 Hz, 2H), 1.44-1.63 (m, 8H), 0.92 (t, J=7.2 Hz, 6H).

Step 3: Hydrogenation of alkyne 45 was conducted following the methodused in Example 2 except that the reaction solvent used was EtOAc andreaction time was 2 h. Alcohol 46 was isolated as an oil and used in thenext step without purification. Yield (0.519 g, quant.): ¹H NMR (400MHz, CDCl₃) δ 9.29 (t, J=5.2 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.05-7.09(m, 2H), 6.99 (d, J=7.2 Hz, 1H), 5.23 (br s, 1H), 4.50 (t, J=6.0 Hz,1H), 3.93 (br s, 1H), 3.20 (q, J=6.8 Hz, 2H), 2.44-2.50 (m, 2H),1.72-1.77 (m, 2H), 1.19-1.33 (m, 10H), 0.82 (t, J=6.8 Hz, 6H).

Step 4: To a solution of alcohol 46 (0.510 g, 1.31 mmol) in 10% H₂O-MeOH(20 mL) was added K₂CO₃ (0.905 g, 6.55 mmol) and the mixture was stirredovernight at room temperature. The mixture was concentrated underreduced pressure then partitioned between EtOAc and water. The combinedorganics were dried over Na₂SO₄ and concentrated under reduced pressure.Purification by flash chromatography (10% 7 M NH₃ in MeOH/CH₂Cl₂) gaveExample 19 as a clear oil. Yield (0.202 g, 53%): ¹H NMR (400 MHz, CDCl₃)δ 7.17 (t, J=7.2 Hz, 1H), 7.12 (m, 1H), 7.07-7.09 (m, 1H), 6.98-7.00 (m,1H), 4.59-4.62 (m, 1H), 3.96 (br s, 1H), 2.57-2.66 (m, 2H), 2.48-2.53(m, 2H), 1.53-1.65 (m, 4H), 1.22-1.36 (m, 10H), 0.84-0.86 (m, 6H).

Example 20 Preparation of 1-(3-(3-aminopropyl)phenethyl)cycloheptanol

1-(3-(3-Aminopropyl)phenethyl)cycloheptanol was prepared following themethod used to prepare Example 7:

Step 1: Coupling of 1-ethynylcycloheptanol with bromide 10 following themethod used to prepare Example 7.

Purification by flash chromatography (20% EtOAc-hexanes) gave2,2,2-trifluoro-N-(3-(3-((1-hydroxycycloheptyl)ethynyl)phenyl)propyl)acetamideas a pale yellow oil. Yield (1.78 g, 60%): ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (s, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.17-7.22 (m, 3H), 5.26 (s, 1H),3.16 (q, J=6.0 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.91-1.97 (m, 2H),1.73-1.79 (m, 4H), 1.45-1.63 (m, 8H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-((1-hydroxycycloheptyl)ethynyl)-phenyl)propyl)acetamidewas conducted following the method used to prepare Example 2 except that5 equivalents of K₂CO₃ were used and the reaction was stirred at roomtemperature overnight. Purification by flash chromatography (10% 7M NH₃in MeOH/CH₂Cl₂) gave2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycycloheptyl)ethyl)phenyl)propyl)acetamideas a clear oil. Yield (0.635 g, 86%): ¹H NMR (400 MHz, DMSO-d₆) δ7.16-7.32 (m, 4H), 5.13 (s, 1H), 4.65 (t, J=6.0 Hz, 1H), 2.56-2.64 (m,2H), 1.44-1.63 (m, 12H), 0.90 (t, J=7.6 Hz, 6H).

Step 3: Hydrogenation of2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycycloheptyl)ethyl)phenyl)propyl)acetamidefollowing the method used to prepare Example 7 gave Example 19 as acolorless oil. Yield (0.305 g, 100%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13(t, J=7.2 Hz, 1H), 6.94-6.98 (m, 3H), 4.01 (br s, 1H), 2.47-2.58 (m,4H), 1.32-1.62 (m, 20H).

Example 21 Preparation of3-(3-(2-(naphthalen-2-yl)ethyl)phenyl)propan-1-amine

3-(3-(2-(Naphthalen-2-yl)ethyl)phenyl)propan-1-amine was preparedfollowing the method shown in scheme 10:

Step 1: To a degassed solution of 3-(3-bromophenyl)propan-1-ol (47)(0.95 g, 4.5 mmol) and 2-methyl-3-butyn-2-ol (48) (1.6 mL, 16 mmol) intriethylamine (25 mL) was added PdCl₂(PPh₃)₃ (0.095 g, 0.14 mmol) andCuI (0.027 g, 0.14 mmol). The resulting mixture was degassed and stirredunder argon at 70° C. for 15 h. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure and dilutedwith EtOAc (50 mL). Trace solids were removed by filtration then thefiltrate was washed with water and brine, dried over Na₂SO₄, andconcentrated under reduced pressure. Purification by flashchromatography (10 to 100% EtOAc-hexanes gradient) gave4-(3-(3-hydroxypropyl)phenyl)-2-methylbut-3-yn-2-ol (49) as a lightbrown oil: Yield (0.78 g, 80%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.18-7.29(m, 4H), 5.46 (s, 1H), 4.48 (t, J=4.0 Hz, 1H), 3.38 (q, J=4.0 Hz, 2H),2.59 (t, J=6.0 Hz, 2H), 2.46 (m, 2H), 1.46 (s, 6H).

Step 2: To a solution of4-(3-(3-hydroxypropyl)phenyl)-2-methylbut-3-yn-2-ol (49) (0.750 g, 3.4mmol) in toluene (50 mL) was added powdered KOH (0.390 g, 7 mmol). Theresulting mixture was heated at reflux for 45 min. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure to 10-15 mL volume and partitioned between EtOAc and water. Thecombined organics were washed with water and brine, dried over MgSO₄ andconcentrated under reduced pressure. Purification by flashchromatography (15% EtOAc-hexanes) gave 3-(3-ethynylphenyl)propan-1-ol(50) as a light brown oil. Yield (0.272 g, 49%).

Step 3: To a degassed solution of alcohol 50 (0.5 g, 3.12 mmol) and2-bromonapthalene (51) (0.54 g, 2.60 mmol) in Et₃N (13 mL) was addedPdCl₂(PPh₃)₂ (0.055 g, 0.078 mmol) and CuI (0.015 g, 0.078 mmol). Thereaction mixture was stirred overnight at 70° C. After cooling to roomtemperature, the mixture was concentrated under reduced pressure. Theresidue was dissolved in EtOAc and the solids filtered off. The filtratewas washed with water and brine, dried over Na₂SO₄ and concentratedunder reduced pressure. Purification by flash chromatography (8%EtOAc-hexanes) provided alcohol 52 as a brown oil. Yield (0.40 g, 45%):¹H NMR (400 MHz, CDCl₃) δ 8.06 (br s, 1H), 7.80-7.83 (m, 2H), 7.58 (dd,J=8.8, 2.0 Hz, 1H), 7.47-7.51 (m, 2H), 7.41-7.43 (m, 2H), 7.26-7.31 (m,2H), 7.18 (d, J=7.6 Hz, 1H), 4.77 (br s, 1H), 4.11 (t, J=6.4 Hz, 2H),2.71 (t, J=7.6 Hz, 2H), 1.99 (quint, J=6.8 Hz, 2H).

Step 4: To a solution of alcohol 52 (0.35 g, 1.22 mmol) in THF (20 mL)was added phthalimide (0.18 g, 1.28 mmol) and PPh₃ (0.40 g, 1.52 mmol).The reaction mixture was cooled to 0° C. and a solution of diisopropylazodicarboxylate (0.32 g, 1.61 mmol) in THF (5 mL) was added dropwise.The reaction was stirred at room temperature for 1 h. The mixture wasconcentrated under reduced pressure and 20% EtOAc-heptane was added. Themixture was sonicated for 10 min then the precipitate was filtered off.The filtrate was concentrated under reduced pressure. Purification byflash chromatography (10% EtOAc-hexanes) gave alkyne 53 as a yellowsolid. Yield (0.40 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=8.0 Hz,1H), 7.82-7.88 (m, 4H), 7.76 (dd, J=7.2, 1.2 Hz, 1H), 7.70 (dd, J=5.2,3.2 Hz, 2H), 7.59-7.64 (m, 1H), 7.52-7.56 (m, 1H), 7.42-7.49 (m, 3H),7.29 (d, J=7.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 3.79 (t, J=7.2 Hz, 2H),2.73 (t, J=7.2 Hz, 2H), 2.09 (quint, J=7.2 Hz, 2H).

Step 5: To a solution of alkyne 53 (0.40 g, 0.96 mmol) in EtOH (4 mL)was added hydrazine hydrate (0.17 mL, 2.89 mmol). The reaction wasstirred at room temperature overnight. Diethyl ether was added and thesolids were removed by filtration. The filtrate was concentrated underreduced pressure. Purification by Prep HPLC using Method 2P gave amine54 as a white solid. Yield (0.12 g, 44%): ¹H NMR (400 MHz, DMSO-d₆) δ8.18 (s, 1H), 7.80-7.95 (m, 3H), 7.69 (br s, 2H), 7.57-7.62 (m, 3H),7.45-7.49 (m, 2H), 7.40 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 2.80(t, J=7.2 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H), 1.87 (quint, J=7.6 Hz, 2H).

Step 6: Hydrogenation of alkyne 54 following the method used in Example13 gave Example 21 trifluoroacetate as a white solid. Yield (0.019 g,23%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.81-7.88 (m, 3H), 7.71 (s, 1H), 7.68(br s, 2H), 7.42-7.50 (m, 3H), 7.22 (t, J=7.4 Hz, 1H), 7.10-7.12 (m,2H), 7.03 (d, J=7.6 Hz, 1H), 3.02-3.06 (m, 2H), 2.94-2.98 (m, 2H), 2.78(t, J=7.4 Hz, 2H), 2.61 (t, J=7.6, 2H), 1.81 (quint, J=7.6 Hz, 2H).

Example 22 Preparation of 3-(3-phenethylphenyl)propan-1-amine

3-(3-Phenethylphenyl)propan-1-amine was prepared following the methodshown in Scheme 11:

Step 1: Coupling of alcohol 47 with phthalimide was conducted followingthe procedure described in Example 13, except that the reaction was runat room temperature. Purification by flash chromatography (6%EtOAc-hexanes) gave phthalimide 55 as a cream-colored solid. Yield (8.6g, 92%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.81-7.87 (m, 4H), 7.44 (s, 1H),7.31-7.33 (m, 1H), 7.19-7.24 (m, 2H), 3.60 (t, J=6.8 Hz, 2H), 2.63 (t,J=7.6 Hz, 2H), 1.87-1.94 (m, 2H).

Step 2: Deprotection of phthalimide 55 following the method used inExample 21, except that the reaction mixture was heated at reflux for1.5 h, gave amine 56 as a yellow oil. This compound was taken on to thenext synthetic step without purification. Yield (5.4 g, 98%).

Step 3: Protection of amine 56 with di-tert-butyl dicarbonate followingthe method used in Example 17 gave carbamate 57 as a light yellow oil.Carbamate 57 was used in the next synthetic step without furtherpurification.

Yield (6.97 g, 86%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.33 (s, 1H), 7.26-7.34(m, 1H), 7.08-7.20 (m, 2H), 4.55 (br s, 1H), 3.15 (q, J=6 Hz, 2H), 2.61(t, J=8.0 Hz, 2H), 1.79 (quint, J=7.6 Hz, 2H), 1.44 (s, 9H).

Step 4: Coupling of phenylacetylene (58) with bromide 57 was conductedfollowing the method used in Example 13. Purification by flashchromatography (5% EtOAc-hexanes) gave tert-butyl3-(3-(phenylethynyl)phenyl)propylcarbamate (59) as a brown oil. Yield(0.32 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J=7.2, 2 Hz, 2H),7.42-7.47 (m, 1H), 7.36-7.38 (m, 1H), 7.20-7.26 (m, 2H), 7.11 (d, J=8.0Hz, 1H), 6.98 (t, J=7.6 Hz, 1H), 6.86 (m, 1H), 4.54 (br s, 1H),3.14-3.17 (m, 2H), 2.63 (quint, J=7.6 Hz, 2H), 1.76-1.86 (m, 2H), 1.38(s, 9H).

Step 5: Deprotection of tert-butyl3-(3-(phenylethynyl)phenyl)propylcarbamate (59) was conducted followingthe procedure used in the preparation of Example 13. Trituration fromdiethyl ether gave 3-(3-(phenylethynyl)phenyl)propan-1-aminehydrochloride (60) as an off white solid. Yield (0.19 g, 73%): ¹H NMR(400 MHz, DMSO-d₆) δ 8.08 (br s, 2H), 7.55-7.57 (m, 1H), 7.21-7.46 (m,6H), 7.21-7.30 (m, 2H), 2.77 (q, J=7.6 Hz, 2H), 2.66 (q, J=7.6 Hz, 2H),1.82-1.93 (m, 2H).

Step 6: Hydrogenation of 3-(3-(phenylethynyl)phenyl)propan-1-amine wasconducted following the method used to prepare Example 18. This compoundwas purified by Prep HPLC using Method 1P to give Example 23trifluoroacetate as a cream-colored solid. Yield (0.080 g, 36%): ¹H NMR(400 MHz, CDCl₃) δ 7.87 (br s, 2H), 7.24-7.28 (3H), 7.16-7.20 (m, 3H),6.93-7.03 (m, 3H), 2.85-2.87 (m, 5H (apparent low integration)), 2.61(t, J=7.6 Hz, 2H), 1.94 (quint, J=7.6 Hz, 2H); ¹³C NMR (300 MHz, CDCl₃)δ 142.20, 141.71, 139.72, 128.62, 128.46, 128.44, 128.30, 126.55,125.88, 125.77, 39.35, 37.84, 37.79, 32.28, 28.90.

Example 23 Preparation of 4-(3-(3-aminopropyl)phenyl)butan-1-ol

4-(3-(3-Aminopropyl)phenyl)butan-1-ol was prepared following the methodused for the preparation of Example 2:

Step 1: Coupling of but-3-yn-1-ol with bromide 10 gave2,2,2-trifluoro-N-(3-(3-(4-hydroxybut-1-ynyl)phenyl)propyl)acetamide asa pale yellow oil. Yield (0.9 g, 62%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40(br s, 1H), 7.15-7.26 (m, 4H), 4.86 (br s, 1H), 3.56 (app t, J=6.8 Hz,2H), 3.16 (q, J=6.8 Hz, 2H), 2.47-2.56 (m, 4H), 1.76 (quint, J=7.6 Hz,2H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(4-hydroxybut-1-ynyl)phenyl)propyl)acetamidefollowing the method used in Example 2, except that the product waspurified by flash chromatography (CH₂Cl₂/EtOH/NH₄OH 85:14:1) gave4-(3-(3-aminopropyl)phenyl)but-3-yn-1-ol as a clear oil. Yield (0.236 g,65%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.12-7.24 (m, 4H), 3.56 (t, J=6.9 Hz,2H), 2.47-2.57 (m, 6H), 1.59 (quint, J=6.9 Hz, 2H).

Step 3: Hydrogenation of 4-(3-(3-aminopropyl)phenyl)but-3-yn-1-olfollowing the method used to prepare example 18 gave Example 23trifluoroacetate as a white solid. Yield (0.040 g, 56%): ¹H NMR (400MHz, DMSO-d₆) δ 7.74 (br s, 3H), 7.20 (t, J=8.0 Hz, 1H), 7.00-7.06 (m,3H), 4.37 (m, 1H), 3.27-3.41 (m, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.45-2.62(m, 4H), 1.78-1.86 (m, 2H), 1.54-1.61 (m, 2H), 1.39-1.46 (m, 2H).

Example 24 Preparation of 3-(3-(2-cyclopentylethyl)phenyl)propan-1-amine

3-(3-(2-Cyclopentylethyl)phenyl)propan-1-amine was prepared followingthe method used for the preparation of Example 22:

Step 1: Coupling ethynylcyclopentane with bromide 57 was conductedfollowing the method used in Example 22.

Purification by flash chromatography (6% EtOAc-hexanes) gave tert-butyl3-(3-(cyclopentylethynyl)phenyl)propylcarbamate as a brown oil. Yield(0.70 g, 84%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.06-7.33 (m, 4H), 2.85(quint, J=7.4 Hz, 1H), 2.57-2.66 (m, 2H), 2.62 (t, J=8.0 Hz, 2H),1.93-2.01 (m, 2H), 1.82 (quint, J=7.6 Hz, 2H), 1.66-1.75 (m, 2H),1.55-1.64 (m, 4H), 1.45 (m, 9H).

Step 2: Deprotection of tert-butyl3-(3-(cyclopentylethynyl)phenyl)propylcarbamate following purificationby preparative HPLC (Method 1P) gave3-(3-(cyclopentylethynyl)phenyl)propan-1-amine trifluoroacetate as awhite solid. Yield (0.22 g, 30%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.68 (brs, 2H), 7.27 (t, J=7.6 Hz, 1H), 7.16-7.24 (m, 3H), 2.85 (quint, J=7.6Hz, 1H), 2.75 (br s, 2H), 2.62 (t, J=7.2 Hz, 2H), 1.93-2.01 (m, 2H),1.82 (quint, J=7.6 Hz, 2H), 1.67-1.71 (m, 2H), 1.56-1.66 (m, 4H).

Step 3: Hydrogenation of 3-(3-(cyclopentylethynyl)phenyl)propan-1-aminefollowing the method used to prepare example 18 gave Example 24trifluoroacetate as a white solid. Yield (80 mg, 79%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.67 (br s, 3H), 7.20 (t, J=8.0 Hz, 1H), 7.00-7.15 (m, 3H),2.78 (t, J=8.4 Hz, 2H), 2.54-2.62 (m, 4H), 1.66-1.85 (m, 4H), 1.42-1.64(m, 7H), 1.18-1.15 (m, 2H).

Example 25 Preparation of 3-(3-(2-cyclohexylethyl)phenyl)propan-1-amine

3-(3-(2-Cyclohexylethyl)phenyl)propan-1-amine was prepared following themethod used for the preparation of Example 22:

Step 1: Coupling of ethynylcyclohexane with bromide 57 was conductedfollowing the method used in Example 22. Purification by flashchromatography (5% EtOAc-hexanes) gave tert-butyl3-(3-(cyclohexylethynyl)phenyl)propylcarbamate as a brown oil. Yield(0.50 g, 57%).

Step 2: Deprotection of tert-butyl3-(3-(cyclohexylethynyl)phenyl)propylcarbamate followed by purificationby preparative HPLC (Method 1P) gave3-(3-(cyclohexylethynyl)phenyl)propan-1-amine trifluoroacetate as acream-colored solid. Yield (0.21 g, 40%): ¹H NMR (400 MHz, DMSO-d₆) δ7.67 (br s, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.17-7.24 (m, 3H), 2.74-2.79(m, 1H), 2.64 (t, J=7.6 Hz, 4H), 1.82 (quint, J=7.2 Hz, 4H), 1.67-1.68(m, 2H), 1.32-1.52 (m, 6H).

Step 3: Hydrogenation of 3-(3-(cyclohexylethynyl)phenyl)propan-1-aminewas conducted following the method used to prepare Example 18.Purification by Prep HPLC using Method 1P gave Example 24trifluoroacetate as a white solid. Yield (0.050 g, 33%): ¹H NMR (400MHz, CDCl₃) δ 7.87 (br s, 3H), 7.16 (t, J=7.6 Hz, 1H), 7.01 (d, J=7.6Hz, 1H), 6.92-6.94 (m, 2H), 2.87 (m, 2H), 2.53-2.62 (m, 4H), 1.63-1.76(m, 5H), 1.43-1.49 (m, 2H), 1.13-1.29 (m, 6H), 0.87-0.96 (m, 2H).

Example 26 Preparation of 3-(3-(3-phenylpropyl)phenyl)propan-1-amine

3-(3-(3-Phenylpropyl)phenyl)propan-1-amine was prepared following themethod used for the preparation of Example 22:

Step 1: Coupling of prop-2-ynylbenzene with bromide 57 was conductedfollowing the method used in Example 22. Purification by flashchromatography (6% EtOAc-hexanes) gave tert-butyl3-(3-(3-phenylprop-1-ynyl)phenyl)propylcarbamate as a brown oil. Yield(0.85 g, 73%): ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.43 (m, 2H), 7.35 (t,J=8.0 Hz, 2H), 7.10-7.28 (m, 5H), 4.52 (br s, 1H), 3.84 (s, 2H),3.14-3.16 (m, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.80 (quint, J=7.6 Hz, 2H),1.48 (s, 9H).

Step 2: Deprotection of tert-butyl3-(3-(3-phenylprop-1-ynyl)phenyl)propylcarbamate followed bypurification by preparative HPLC (Method-001P) gave3-(3-(3-phenylprop-1-ynyl)phenyl)propan-1-amine trifluoroacetate as awhite solid. Yield (0.45 g, 51%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.69 (brs, 2H), 7.35-7.42 (m, 4H), 7.25-7.31 (m, 4H), 7.20-7.22 (m, 1H), 3.89(s, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.82 (quint,J=7.6 Hz, 2H).

Step 3: Hydrogenation of 3-(3-(3-phenylprop-1-ynyl)phenyl)propan-1-aminetrifluoroacetate following the method used to prepare Example 18 gaveExample 26 which was HPLC purified using Method 1P to give Example 26trifluoroacetate as a colorless oil. Yield (0.180 g, 88%): ¹H NMR (400MHz, DMSO-d₆) δ 7.69 (br s, 3H), 7.29 (t, J=7.2 Hz, 2H), 7.16-7.24 (m,4H), 7.01-7.05 (m, 3H), 2.88 (t, J=8.0 Hz, 2H), 2.56-2.62 (m, 6H),1.88-1.91 (m, 4H).

Example 27 Preparation of 3-(3-pentylphenyl)propan-1-amine

3-(3-Pentylphenyl)propan-1-amine was prepared following the method usedfor the preparation of Example 22:

Step 1: Coupling of 1-pent-1-yne with bromide 57 was conducted followingthe method used in Example 22.

Purification by flash chromatography (5% EtOAc-hexanes) gave tert-butyl3-(3-(pent-1-ynyl)phenyl)propylcarbamate as a brown oil. Yield (0.35 g,58%): ¹H NMR (400 MHz, CDCl₃) δ 7.07-7.33 (m, 4H), 4.52 (br s, 1H),3.14-3.15 (m, 2H), 2.58-2.66 (m, 2H), 2.38 (t, J=7.2 Hz, 2H), 1.79(quint, J=7.6 Hz, 2H), 1.64 (q, J=7.2 Hz, 2H), 1.45 (s, 9H), 1.05 (t,J=6.8 Hz, 3H).

Step 2: Deprotection of tert-butyl3-(3-(pent-1-ynyl)phenyl)propylcarbamate followed by purification bypreparative HPLC (Method 1P) gave3-(3-(pent-1-ynyl)phenyl)propan-1-amine trifluoroacetate as a whitesolid. Yield (0.17 g, 32%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (br s, 2H),7.28 (t, J=7.6 Hz, 1H), 7.17-7.25 (m, 3H), 2.76 (t, J=7.2 Hz, 2H), 2.62(t, J=7.2 Hz, 2H), 2.39 (t, J=6.8 Hz, 2H), 1.82 (quint, J=7.6 Hz, 2H),1.51-1.60 (m, 2H), 1.00 (t, J=7.6 Hz, 3H).

Step 3: Hydrogenation of 3-(3-(pent-1-ynyl)phenyl)propan-1-aminetrifluoroacetate following the method used to prepare example 18 gaveExample 27 which was HPLC purified to give Example 27 trifluoroacetateas a cream-colored solid. Yield (0.050 g, 20%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.72 (br s, 3H), 7.20 (t, J=7.6 Hz, 1H), 7.00-7.03 (m, 3H),2.88 (m, 2H), 2.60 (t, J=7.6 Hz, 2H), 2.46-2.56 (m, 2H), 1.78-1.85 (m,2H), 1.52-1.59 (m, 2H), 1.22-1.34 (m, 4H), 0.86 (t, J=7.2 Hz, 3H).

Example 28 Preparation of 3-(3-hexylphenyl)propan-1-amine

3-(3-Hexylphenyl)propan-1-amine was prepared following the method usedfor the preparation of Example 22:

Step 1: Coupling of hex-1-yne with bromide 57 was conducted followingthe method used in Example 22.

Purification by flash chromatography (5% EtOAc-hexanes) gave tert-butyl3-(3-(hex-1-ynyl)phenyl)propylcarbamate as a brown oil. Yield (0.64 g,64%).

Step 2: Deprotection of tert-butyl3-(3-(hex-1-ynyl)phenyl)propylcarbamategave followed by purification bypreparative HPLC (Method 4P) gave 3-(3-(hex-1-ynyl)phenyl)propan-1-aminehydrochloride as a white solid. Yield (0.17 g, 33%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.71 (br s, 2H), 7.28 (t, J=7.2 Hz, 1H), 7.17-7.25 (m, 3H),2.76 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.42 (t, J=7.0 Hz, 2H),1.82 (quint, J=7.6 Hz, 2H), 1.52 (quint, J=7.0 Hz, 2H), 1.44 (quint,J=7.0 Hz, 2H), 0.92 (t, J=7.6 Hz, 3H).

Step 3: Hydrogenation of 3-(3-(hex-1-ynyl)phenyl)propan-1-aminehydrochloride following the method used to prepare Example 18 gaveExample 28 hydrochloride as a colorless oil. Yield (0.085 g, 98%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.76 (br s, 3H), 7.20 (t, J=7.6 Hz, 1H),7.00-7.03 (m, 3H), 2.78 (t, J=7.6 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H),2.46-2.56 (m, 2H), 1.82 (quint, J=7.6 Hz, 2H), 1.51-1.56 (m, 2H),1.20-1.30 (m, 6H), 0.85 (t, J=7.2 Hz, 3H).

Example 29 Preparation of 3-(3-(3,3-dimethylbutyl)phenyl)propan-1-amine

3-(3-(3,3-Dimethylbutyl)phenyl)propan-1-amine was prepared following themethod used for the preparation of Example 22:

Step 1: Coupling of 3,3-dimethylbut-1-yne with bromide 57 was conductedfollowing the method used in Example 22. Purification by flashchromatography (6% EtOAc-hexanes) gave tert-butyl3-(3-(3,3-dimethylbut-1-ynyl)phenyl)propylcarbamate as a brown oil.Yield (0.43 g, 54%).

Step 2: Deprotection of tert-butyl3-(3-(3,3-dimethylbut-1-ynyl)phenyl)propylcarbamate followingpurification by preparative HPLC (Method 1P) gave3-(3-(3,3-dimethylbut-1-ynyl)phenyl)propan-1-amine trifluoroacetate as apale yellow solid. Yield (0.08 g, 18%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.79(br s, 2H), 7.27 (t, J=7.6 Hz, 1H), 7.16-7.22 (m, 3H), 2.75-2.77 (m,2H), 2.61 (t, J=7.6 Hz, 2H), 1.82 (quint, J=7.2 Hz, 2H), 1.29 (s, 9H).

Step 3: Hydrogenation of 3-(3-(hex-1-ynyl)phenyl)propan-1-aminetrifluoroacetate following the method used to prepare Example 18 gaveExample 29 trifluoroacetate as a cream-colored solid. Yield (0.040 g,50%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.69 (br s, 3H), 7.18-7.22 (m, 1H),6.99-7.28 (m, 3H), 2.78 (t, J=5.2 Hz, 2H), 2.61 (t, J=5.2 Hz, 2H),2.50-2.55 (m, 2H), 1.79-1.84 (m, 2H), 1.41-1.46 (m, 2H), 0.95 (s, 9H).

Example 30 Preparation of 6-(3-(3-aminopropyl)phenyl)hexan-1-ol

6-(3-(3-Aminopropyl)phenyl)hexan-1-ol was prepared following the methodused for the preparation of Example 22:

Step 1: Coupling of hex-5-yn-1-ol with bromide 57 was conductedfollowing the method used in Example 22.

Purification by flash chromatography (30% EtOAc-hexanes) gave tert-butyl3-(3-(6-hydroxyhex-1-ynyl)phenyl)propylcarbamate as a white solid. Yield(0.350 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.23 (m, 3H), 7.07-7.10(m, 1H), 6.81-6.84 (m, 1H), 4.53 (br s, 1H), 3.72 (q, J=6.0 Hz, 2H),3.10-3.18 (m, 2H), 2.60 (t, J=8.0 Hz, 2H), 2.46 (t, J=6.8 Hz, 2H),1.63-1.83 (m, 6H), 1.44 (s, 9H).

Step 2: Deprotection of tert-butyl3-(3-(6-hydroxyhex-1-ynyl)phenyl)propylcarbamate following purificationby prep HPLC using Method 1P gave3-(3-(3,3-dimethylbut-1-ynyl)phenyl)propan-1-amine trifluoroacetate as awhite solid. Yield (0.140 g, 34%): ¹H NMR (400 MHz, CDCl₃) δ 7.21 (d,J=7.6 Hz, 2H), 7.17 (t, J=7.6 Hz, 1H), 7.07 (dm, J=7.2 Hz, 1H), 3.68 (t,J=6.4 Hz, 2H), 2.95 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6, 2H), 2.43 (t,J=6.4, 2H), 2.06 (quint, J=7.6 Hz, 2H), 1.71-1.79 (m, 2H), 1.61-1.68 (m,2H).

Step 3: 6-(3-(3-Aminopropyl)phenyl)hex-5-yn-1-ol trifluoroacetate washydrogenated following the procedure used in Example 18 to give Example30 trifluoroacetate as a white solid. Yield (33%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.88 (br s, 3H), 7.20 (t, J=7.6 Hz, 1H), 6.95-7.20 (m, 3H),4.38 (br s, 1H), 3.37 (t, J=6.0 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.59(t, J=7.6 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 1.80-1.87 (m, 2H), 1.53-1.58(m, 2H), 1.38-1.42 (m, 2H), 1.24-1.32 (m, 4H).

Example 31 Preparation of 3-(3-(2-methylphenethyl)phenyl)propan-1-amine

3-(3-(2-Methylphenethyl)phenyl)propan-1-amine was prepared following themethod shown in scheme 12:

Step 1: Coupling of alcohol 50 with phthalimide following the proceduredescribed in Example 21 gave alkyne 61 as a yellow solid Yield (6.0 g,76%): ¹H NMR (400 MHz, CDCl₃) δ 7.83 (dd, J=5.2, 2.8 Hz, 2H), 7.70 (dd,J=5.6, 3.2 Hz, 2H), 7.33 (s, 1H), 7.29-7.24 (m, 1H), 7.16-7.22 (m, 2H),3.74 (t, J=7.2 Hz, 2H), 3.04 (s, 1H), 2.66 (t, J=8.0 Hz, 2H), 2.02(quint, J=7.2 Hz, 2H).

Step 2: To a degassed solution of alkyne 61 (0.6 g, 2.07 mmol) and2-iodo toluene (0.543 g, 2.49 mmol) in triethyl amine (25 mL) was addedPdCl₂(PPh₃)₂ (0.0435 g, 0.062 mmol) and CuI (0.0117 g, 0.062 mmol). Thereaction was stirred overnight at 70° C. After cooling to roomtemperature, the mixture was concentrated under reduced pressure.

The residue was dissolved in EtOAc and the solids were removed byfiltration. The filtrate was washed with water and brine, dried overNa₂SO₄ and concentrated under reduced pressure. Purification by flashchromatography (15% EtOAc-hexanes) provided alkyne 62 as a brown oil.Yield (0.48 g, 61%): ¹H NMR (400 MHz, CDCl₃) δ 7.83 (dd, J=5.6, 3.2 Hz,2H), 7.76 (dd, J=5.6, 3.2 Hz, 2H), 7.48 (d, J=7.2 Hz, 1H), 7.37 (m, 1H),7.31-7.32 (m, 1H), 7.15-7.24 (m, 5H), 3.77 (t, J=7.2 Hz, 2H), 2.70 (t,J=7.2 Hz, 2H), 2.50 (s, 3H), 2.02-2.09 (m, 2H).

Step 3: To alkyne 62 (0.48 g, 1.26 mmol) in EtOH (25 mL) was addedhydrazine hydrate (0.23 mL, 3.79 mmol). The reaction mixture was stirredat room temperature overnight. Diethyl ether was added to the reactionmixture. The solid formed was filtered off and the filtrate wasconcentrated under reduced pressure. Purification by prep HPLC (Method2P) gave amine 63 as a pale yellow oil. Yield (80 mg, 25%): ¹H NMR (400MHz, DMSO-d₆) δ 7.24-7.53 (m, 8H), 2.65 (t, J=8.0 Hz, 2H), 2.57 (t,J=6.8 Hz, 2H), 2.49 (s, 3H), 1.65-1.72 (m, 2H).

Step 4: 3-(3-(o-Tolylethynyl)phenyl)propan-1-amine was hydrogenatedfollowing the method used in Example 17 to give Example 31 which wasHPLC purified to give Example 31 trifluoroacetamide as a whitesemi-solid. Yield (0.021 g, 30%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (brs, 3H), 7.19 (t, J=7.6 Hz, 1H), 6.99-7.13 (m, 7H), 2.72-2.83 (m, 6H),2.57 (t, J=7.6 Hz, 2H), 2.22 (s, 3H), 1.74-1.81 (m, 2H).

Example 32 Preparation of3-(3-(2-(biphenyl-3-yl)ethyl)phenyl)propan-1-amine

3-(3-(2-(Biphenyl-3-yl)ethyl)phenyl)propan-1-amine was preparedfollowing the method used for the preparation of Example 21:

Step 1: Coupling of alcohol 50 with 3-bromobiphenyl was conductedfollowing the method described in Example 21 to give3-(3-(biphenyl-3-ylethynyl)phenyl)propan-1-ol. Purification by flashchromatography (5% EtOAc-hexanes) gave a brown oil. Yield (0.560 g,67%): ¹H NMR (400 MHz, CDCl₃) δ 7.78 (br s, 1H), 7.61 (d, J=7.2 Hz, 2H),7.56 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.37-7.48 (m, 6H), 7.29(d, J=7.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 3.70 (dt, J=6.2, 5.2 Hz, 2H),2.73 (t, J=7.6 Hz, 2H), 1.92 (quint, J=6.8 Hz, 2H), 1.27 (t, J=5.2 Hz,1H).

Step 2: Coupling of 3-(3-(biphenyl-3-ylethynyl)phenyl)propan-1-ol withphthalimide was conducted following the method described in Example 21.Purification by flash chromatography (6% EtOAc-hexanes) gave2-(3-(3-(biphenyl-3-ylethynyl)phenyl)propyl)isoindoline-1,3-dione. Yield(0.320 g, 42%): ¹H NMR (400 MHz, CDCl₃) δ 7.84 (dd, J=5.6, 3.2 Hz, 2H),7.77 (m, 1H), 7.71 (dd, J=5.6, 3.2 Hz, 2H), 7.61-7.63 (m, 2H), 7.32-7.57(m, 8H), 7.18-7.25 (m, 2H), 3.77 (t, J=7.2 Hz, 2H), 2.70 (t, J=7.2 Hz,2H), 2.02-2.09 (m, 2H).

Step 3: Deprotection of2-(3-(3-(biphenyl-3-ylethynyl)phenyl)propyl)isoindoline-1,3-dionefollowing the method described in Example 21 followed by purification bypreparative HPLC (Method 1P) gave3-(3-(Biphenyl-3-ylethynyl)phenyl)propan-1-amine trifluoroacetatetrifluoroacetate as a white sticky solid. Yield (0.16 g, 52%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.83 (br s, 1H), 7.71-7.15 (m, 3H), 7.67 (br s,2H), 7.38-7.55 (m, 8H), 7.28-7.30 (m, 1H), 2.77-2.82 (m, 2H), 2.68 (t,J=7.2 Hz, 2H), 1.86 (quint, J=7.6 Hz, 2H).

Step 4: 3-(3-(Biphenyl-3-ylethynyl)phenyl)propan-1-aminetrifluoroacetate was hydrogenated using the method in Example 13 to giveExample 32 trifluoroacetate as a white solid. Yield (0.019 g, 23%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.58-7.60 (m, 2H), 7.40-7.45 (m, 4H), 7.30-7.34(m, 4H), 7.12-7.20 (m, 2H), 6.96-7.04 (m, 3H), 2.84-2.93 (m, 6H),2.48-2.53 (m, 2H), 1.52-1.11 (m, 2H).

Example 33 Preparation of 3-(3-(6-methoxyhexyl)phenyl)propan-1-amine

3-(3-(6-Methoxyhexyl)phenyl)propan-1-amine was prepared following themethod used for the preparation of Example 22:

Step 1: Aryl bromide 57 was coupled with 6-methoxyhex-1-yne followingthe method used for the preparation of Example 13. Purification by flashchromatography (10% EtOAc-hexanes) gave tert-butyl3-(3-(6-methoxyhex-1-ynyl)phenyl)propylcarbamate as a brown oil. Yield(0.20 g, 36%).

Step 2: tert-Butyl 3-(3-(6-methoxyhex-1-ynyl)phenyl)propylcarbamate wasdeprotected following the method used in Example 13 except that CH₂Cl₂was used as a cosolvent in the reaction (HCl-dioxane solution: CH₂Cl₂7:5). Purification by prep HPLC (Method 2P) gave3-(3-(6-methoxyhex-1-ynyl)phenyl)propan-1-amine hydrochloride as an offwhite solid. Yield (0.050 g, 30%): ¹H NMR (400 MHz, CDCl₃) δ 8.37 (br s,3H), 7.10-7.24 (m, 4H), 4.02 (t, J=6.4 Hz, 2H), 3.78 (s, 3H), 2.98 (t,J=7.6 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.6 Hz, 2H), 2.04-2.12(m, 2H), 1.82-1.89 (m, 2H), 1.63-1.73 (m, 2H).

Step 3: 3-(3-(6-Methoxyhexyl)phenyl)propan-1-amine hydrochloride washydrogenated using the method in Example 17 to give Example 33hydrochloride as a white semi-solid. Yield (0.025 g, 82%): ¹H NMR (400MHz, DMSO-d₆) δ 7.89 (br s, 3H), 7.16 (t, J=7.6 Hz, 1H), 6.96-7.01 (m,3H), 4.02 (t, J=6.8 Hz, 2H), 3.64 (s, 3H), 2.72 (t, J=7.6 Hz, 2H), 2.57(t, J=7.6 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H), 1.76-1.83 (m, 2H), 1.48-1.57(m, 4H), 1.25-1.33 (m, 4H).

Example 34 Preparation of 3-(3-(octan-4-yl)phenyl)propan-1-amine

3-(3-(Octan-4-yl)phenyl)propan-1-amine was prepared following the methodshown in scheme 13:

Step 1: To a −78° C. solution of compound 57 (0.650 g, 2.07 mmol, crude)in anhydrous THF (20 mL) was added MeLi (1.36 mL of a 1.6 M solution indiethyl ether, 2.17 mmol) and the mixture was stirred for 10 min.tert-Butyl lithium (2.5 mL of a 1.7 M solution in pentane, 4.24 mmol)was added and the reaction mixture was stirred at −78° C. for 45 min.5-Nonanone (0.324 g, 2.28 mmol) was added to the mixture. After allowingthe mixture to warm to room temperature, the reaction was quenched withthe addition of saturated aqueous NH₄Cl (15 mL) and the pH was adjustedto 5 with 1M HCl. The mixture was extracted with EtOAc and the combinedorganics were dried over Na₂SO₄ and concentrated under reduced pressureto give alcohol 64 as an oil. Yield (0.090 g, 12%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.14-7.19 (m, 3H), 6.97 (d, J=8.0 Hz, 1H), 6.87 (t, J=4.0 Hz,1H), 4.48 (s, 1H), 2.92 (q, J=8.0 Hz, 2H), 2.53 (t, J=8.0 Hz, 2H),1.59-1.74 (m, 6H), 1.37 (s, 9H), 1.15-1.23 (m, 6H), 0.84-0.91 (m, 2H),0.77 (t, J=8.0 Hz. 6H).

Step 2: A solution of alcohol 64 (0.081 g, 0.215 mmol) in HCl (2 mL of a4.2 M solution in EtOAc, 8.4 mmol) was stirred at room temperatureovernight. After concentration under reduced pressure, alkene 65hydrochloride was obtained as an oil and used without purification.(Yield 0.066 g, quant.): ¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (br s, 3H),7.11-7.37 (m, 3H), 7.07 (d, J=8.0 Hz, 1H), 5.63 (t, J=8.0 Hz, 1H),2.77-2.80 (m, 2H), 2.64 (t, J=8.0 Hz, 2H), 2.47 (t, J=8.0 Hz, 2H), 2.15(q, J=8.0 Hz, 2H), 1.81-1.91 (m, 2H), 1.44 (q, J=8.0 Hz, 2H), 1.17-1.27(m, 4H), 0.93 (t, J=8.0 Hz, 3H), 0.83 (t, J=8.0 Hz, 3H).

Step 3: Hydrogenation of compound 65 was conducted following the methodused in Example 2 except that EtOAc was used as the solvent.Purification by flash chromatography (10% 7M NH₃ in MeOH—CH₂Cl₂) gaveExample 34 as an oil. Yield (0.013 g, 30%): ¹H NMR (400 MHz, CDCl₃) δ7.21 (t, J=8.0 Hz, 1H), 6.96-7.03 (m, 3H), 2.75 (t, J=8.0 Hz, 2H), 2.65(t, J=8.0 Hz, 2H), 2.41-2.48 (m, 1H), 1.75-1.84 (m, 2H), 1.48-1.67 (m,4H), 1.44 (br s, 2H), 1.05-1.34 (m, 8H), 0.84 (t, J=8.0 Hz, 6H).

Example 35 Preparation of 3-(3-(4-phenylbutyl)phenyl)propan-1-amine

3-(3-(4-Phenylbutyl)phenyl)propan-1-amine was prepared following themethod used in Example 22.

Step 1: Aryl bromide 57 was coupled with but-3-ynylbenzene following themethod used in Example 22.

Purification by flash chromatography (10% EtOAc-hexanes) gave tert-butyl3-(3-(4-phenylbut-1-ynyl)phenyl)propylcarbamate as a brown oil. Yield(0.40 g, 82%).

Step 2: tert-Butyl 3-(3-(4-phenylbut-1-ynyl)phenyl)propylcarbamate wasdeprotected following the method used in Example 22 to give3-(3-(4-phenylbut-1-ynyl)phenyl)propan-1-amine hydrochloride as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.74 (br s, 3H), 7.14-7.28 (m, 9H),2.82 (t, J=7.2 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.2 Hz, 2H),2.58 (t, J=7.6 Hz, 2H), 1.78 (quint, J=7.6 Hz, 2H).

Step 3: 3-(3-(4-Phenylbut-1-ynyl)phenyl)propan-1-amine hydrochloride washydrogenated following the method used in Example 17, except that thereaction was time was 2 h, to give Example 35 hydrochloride as a whitesolid.

Yield (0.040 g, 49%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (br s, 3H), 7.24(t, J=7.6 Hz, 2H), 7.12-7.19 (m, 4H), 6.98-6.99 (m, 3H), 2.73 (t, J=7.6,2H), 2.56-2.59 (m, 6H), 1.77-1.84 (m, 2H), 1.54-1.55 (m, 4H).

Example 36 Preparation of 2-(3-(2-(pyridin-3-yl)ethyl)phenoxy)ethanamine

2-(3-(2-(Pyridin-3-yl)ethyl)phenoxy)ethanamine was prepared followingthe method shown in scheme 14:

Step 1: Coupling of bromide 26 with 2-methylbut-3-yn-2-ol (48) followingthe method used in Example 13 gave alkyne 66 as a buff-colored solid.Yield (0.90 g, 90%): ¹H NMR (400 MHz, CDCl₃): δ 7.21 (t, J=8.0 Hz, 1H),7.02 (d, J=7.6 Hz, 1H), 6.93-6.95 (m, 1H), 6.85 (ddd, J=8.4, 2.8, 0.8Hz, 1H), 4.97 (br s, 1H), 4.01 (t, J=5.2 Hz, 2H), 3.51-3.52 (m, 2H),1.62, (s, 6H), 1.56 (s, 9H).

Step 2: Treatment of alkyne 66 with KOH following the method used inExample 21 gave alkyne 67 as a brown oil. Yield (0.20 g, 80%): ¹H NMR(400 MHz, CDCl₃) δ 7.23 (d, J=8.0 Hz, 1H), 7.10 (dt, J=7.6, 1.2 Hz, 1H),7.00-7.02 (m, 1H), 6.90 (ddd, J=8.4, 2.8, 0.8 Hz, 1H), 4.97 (br s, 1H),4.01 (t, J=5.2 Hz, 2H), 3.49-3.54 (m, 2H), 3.06 (s, 1H), 1.45 (s, 9H).

Step 3: Coupling of alkyne 67 with 3-bromopyridine following the methodused in Example 13 gave alkyne 68 as a brown oil. Yield (0.340 g, 44%).¹H NMR (400 MHz, CDCl₃) δ 8.76 (d, J=1.4 Hz, 1H), 8.55 (dd, J=4.8, 1.2Hz, 1H), 7.81 (dt, J=8.0, 1.6 Hz, 1H), 7.29 (t, J=4.4 Hz, 1H), 7.28 (s,1H), 7.16 (d, J=8.0 Hz, 1H), 7.06 (br s, 1H), 6.92 (dd, J=8.4, 2.8 Hz,1H), 4.05 (t, J=5.2 Hz, 2H), 3.54 (q, J=5.2 Hz, 2H), 1.46 (s, 9H)

Step 4: Deprotection of alkyne 68 with HCl-dioxane following the methodused in Example 13 gave amine 69 hydrochloride as an off white solid.Yield (0.230 g, 83%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (br s, 1H), 8.60(dd, J=4.8, 1.6 Hz, 1H), 8.11 (br s, 3H), 8.02-8.04 (m, 1H), 7.51 (dd,J=8.0, 5.2 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.18(d, J=1.6 Hz, 1H), 7.06 (dd, J=8.4, 2.4 Hz, 1H), 4.20 (t, J=4.8 Hz, 2H),3.19 (dd, J=10.4, 5.6 Hz, 2H).

Step 5: Hydrogenation of amine 69 hydrochloride was conducted followingthe method used in Example 35. After stirring for 2 h, the solids wereremoved by filtration. The filtrate was concentrated under reducedpressure and the residue was dissolved in concentrated ammoniumhydroxide. The aqueous solution was extracted with CH₂Cl₂. The combinedorganics were concentrated under reduced pressure to give Example 36 asa colorless oil. Yield (0.080 g, 39%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.39(s, 1H), 8.36 (d, J=4.4 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.26 (dd,J=7.6, 4.8, 1H), 7.14 (t, J=8.0, 1H), 6.71-6.77 (m, 3H), 3.85 (t, J=5.6,2H), 2.82-2.84 (m, 6H).

Example 37 Preparation of 2-(3-(2-(pyridin-2-yl)ethyl)phenoxy)ethanamine

2-(3-(2-(Pyridin-2-yl)ethyl)phenoxy)ethanamine was prepared followingthe method used in Example 36:

Step 1: Coupling of alkyne 67 with 2-bromopyridine was conductedfollowing the method used in Example 13. Purification by flashchromatography (20% EtOAc-hexanes) gave tert-butyl2-(3-(pyridin-2-ylethynyl)phenoxy)ethylcarbamate as a yellow oil. Yield(0.50 g, 64%). ¹H NMR (400 MHz, CDCl₃): δ 8.63 (d, J=4.0 Hz, 1H), 7.69(dt, J=7.6, 1.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.24-7.26 (m, 2H), 7.21(dt, J=8.0, 1.2 Hz, 1H), 7.12-7.13 (m, 1H), 6.93 (ddd, J=8.0, 2.4, 1.2Hz, 1H), 4.98 (br s, 1H), 4.03 (t, J=5.2, 2H), 3.54-3.56 (m, 2H), 1.46(s, 9H).

Step 2: Deprotection of tert-butyl2-(3-(pyridin-2-ylethynyl)phenoxy)ethylcarbamate with HCl-dioxanefollowing the method used in Example 13 gave2-(3-(pyridin-2-ylethynyl)phenoxy)ethanamine hydrochloride as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (dt, J=5.2, 0.8 Hz, 1H), 8.20(br s, 3H), 7.92 (dt, J=8.0, 2.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.47(ddd, J=7.6, 5.2, 1.2 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 7.19-7.20 (m, 1H), 7.08 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 4.21 (t,J=5.2 Hz, 2H), 3.18 (dt, J=5.6, 5.2 Hz, 2H).

Step 3: Hydrogenation of 2-(3-(pyridin-2-ylethynyl)phenoxy)ethanaminehydrochloride following the method used in Example 17, except that thereaction time was 3 h, gave Example 37 hydrochloride as a white solid.Yield (0.150 g, 73%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (d, J=5.2 Hz,1H), 8.26 (br s, 4H), 7.75 (d, J=7.6 Hz, 1H), 7.69 (t, J=6.4 Hz, 1H),7.20 (t, J=8.0 Hz, 1H), 6.91 (s, 1H), 6.84 (d, J=7.6, 1H), 6.80 (dd,J=8.0, 2.0 Hz, 1H), 4.15 (t, J=4.8 Hz, 2H), 3.27 (t, J=8.0 Hz, 2H), 3.17(d, J=4.4 Hz, 1H), 3.15 (d, J=4.4 Hz, 1H), 3.03 (t, J=8.0 Hz, 2H).

Example 38 Preparation of2-(3-(2-(thiophen-2-yl)ethyl)phenoxy)ethanamine

2-(3-(2-(Thiophen-2-yl)ethyl)phenoxy)ethanamine was prepared followingthe method used in Example 36:

Step 1: Coupling of alkyne 67 with 2-bromothiophene was conductedfollowing the method used in Example 13.

Purification by flash chromatography (5% EtOAc-hexanes) gave tert-butyl2-(3-(thiophen-2-ylethynyl)phenoxy)ethylcarbamate as a brown oil. Yield(0.605 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 17.30 (dd, J=5.2, 1.2 Hz, 1H),7.28-7.29 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.12 (dt, J=7.6, 1.2 Hz, 1H),7.03-7.04 (m, 1H), 7.02 (dd, J=5.2, 3.6 Hz, 1H), 6.89 (ddd, J=8.0, 2.4,0.8 Hz, 1H), 4.99 (br s, 1H), 4.04 (t, J=4.8 Hz, 2H), 3.55 (dd, J=10.0,5.2 Hz, 2H), 1.46 (s, 9H).

Step 2: Deprotection of tert-butyl2-(3-(thiophen-2-ylethynyl)phenoxy)ethylcarbamate with HCl-dioxanefollowing the method used in Example 13 gave2-(3-(thiophen-2-ylethynyl)phenoxy)ethanamine hydrochloride as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (br s, 3H), 7.66 (dd, J=5.2, 1.2Hz, 1H), 7.40 (dd, J=3.6, 1.2 Hz, 1H), 7.14 (dd, J=7.6, 1.2 Hz, 1H),7.10-7.12 (m, 2H), 7.03 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 4.19 (t, J=5.2Hz, 2H), 3.17 (t, J=5.2, 2H).

Step 3: Hydrogenation of 2-(3-(thiophen-2-ylethynyl)phenoxy)ethanaminehydrochloride following the method used in Example 13 gave Example 38hydrochloride as a white solid. Yield (0.15 g, 95%): ¹H NMR (400 MHz,DMSO-d₆) δ 8.02 (br s, 3H), 7.27 (dd, J=5.2, 1.2 Hz, 1H), 7.18 (t, J=8.0Hz, 1H), 6.89 (dd, J=5.2, 3.2 Hz, 1H), 6.81-6.84 (m, 3H), 6.77 (dd,J=8.4, 1.6 Hz, 1H), 4.11 (t, J=5.2 Hz, 2H), 3.16 (t, J=5.2 Hz, 2H), 3.07(t, J=7.6 Hz, 2H), 2.87 (t, J=7.6 Hz, 2H).

Example 39 Preparation of 5-(3-(3-aminopropyl)phenethyl)nonan-5-ol

5-(3-(3-Aminopropyl)phenethyl)nonan-5-ol was prepared following themethod used in Example 2.

Step 1: Coupling of 3-ethynylnonan-5-ol with bromide 10 gaveN-(3-(3-(3-butyl-3-hydroxyhept-1-ynyl)phenyl)propyl)-2,2,2-trifluoroacetamideas a brown oil. Yield (0.346 g, 22%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40(br s, 1H), 7.14-7.26 (m, 4H), 5.11 (s, 1H), 2.56 (t, J=7.6 Hz, 2H),2.47 (m, 2H), 1.43-1.62 (m, 14H), 0.88 (t, J=7.2 Hz, 6H).

Step 2: Deprotection ofN-(3-(3-(3-butyl-3-hydroxyhept-1-ynyl)phenyl)propyl)-2,2,2-trifluoroacetamidegave 5-((3-(3-aminopropyl)phenyl)ethynyl)nonan-5-ol as a light yellowoil. Yield (0.219 g, 84%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22-7.26 (m,1H), 7.14-7.17 (m, 3H), 5.11 (s, 1H), 2.56 (t, J=7.6 Hz, 2H), 2.49 (t,J=6.8 Hz, 2H), 1.25-1.62 (m, 14H), 0.88 (t, J=7.2 Hz, 6H).

Step 3: Hydrogenation of 5-((3-(3-aminopropyl)phenyl)ethynyl)nonan-5-olgave Example 39 as a colorless oil. Yield (0.133 g, 69%): ¹H NMR (400MHz, CDCl₃) δ 7.18 (t, J=8.0 Hz, 1H), 6.97-7.03 (m, 3H), 2.72 (t, J=5.2Hz, 2H), 2.56-2.65 (m, 4H), 1.68-1.80 (m, 4H), 1.45-1.52 (m, 4H),1.24-1.38 (m, 11H), 0.91 (t, J=6.8 Hz, 6H). ESI MS m/z 306.7 [M+H]⁺,288.6 [M+H−H₂O]⁺.

Example 40 Preparation of3-(3-(3-methoxy-3-propylhexyl)phenyl)propan-1-amine

3-(3-(3-Methoxy-3-propylhexyl)phenyl)propan-1-amine was preparedfollowing the method used in Example 2.

Step 1: Coupling of 4-ethynyl-4-methoxyheptane with bromide 10 gave2,2,2-trifluoro-N-(3-(3-(3-methoxy-3-propylhex-1-ynyl)phenyl)propyl)acetamideas a light yellow oil. Yield (0.596 g, 93%): ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (br s, 1H), 7.18-7.29 (m, 4H), 3.25 (s, 3H), 3.14-3.20 (m, 2H),2.56 (t, J=7.6 Hz, 2H), 1.73-1.80 (m, 2H), 1.64 (t, J=8.4 Hz, 4H),1.34-1.44 (m, 4H), 0.88 (t, J=7.2 Hz, 6H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-methoxy-3-propylhex-1-ynyl)phenyl)propyl)acetamidegave 3-(3-(3-methoxy-3-propylhex-1-ynyl)phenyl)propan-1-amine as a clearoil. Yield (0.341 g, 93%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.27-7.18 (m,4H), 3.25 (s, 3H), 2.56 (t, J=7.6 Hz, 2H), 2.47 (t, J=6.8 Hz, 2H),1.56-1.66 (m, 6H), 1.32-1.44 (m, 6H), 0.88 (t, J=7.2 Hz, 6H).

Step 3: Hydrogenation of3-(3-(3-methoxy-3-propylhex-1-ynyl)phenyl)propan-1-amine gave Example 40as a colorless oil. Yield (0.188 g, 71%): ¹H NMR (400 MHz, CDCl₃) δ 7.18(t, J=8.0 Hz, 1H), 6.95-7.04 (m, 3H), 3.16 (s, 3H), 2.72 (t, J=7.2 Hz,2H), 2.62 (t, J=8.0 Hz, 2H), 2.48-2.55 (m, 2H), 1.64-1.80 (m, 4H),1.41-1.48 (m, 4H), 1.24-1.35 (m, 4H), 1.20 (br s, 2H), 0.92 (t, J=7.2Hz, 6H). ESI MS m/z 292.5 [M+H]+.

Example 41 Preparation of 1-(3-(3-aminopropyl)phenyl)-3-methylhexan-3-ol

1-(3-(3-Aminopropyl)phenyl)-3-methylhexan-3-ol was prepared followingthe method used in Example 2.

Step 1: Coupling of 3-methylhex-1-yn-3-ol with bromide 10 gave2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-methylhex-1-ynyl)phenyl)propyl)acetamidecontaminated with alkyne dimer. Yield (0.699 g, >100%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.40 (br s, 1H), 7.25 (dd, J=8.8, 7.2 Hz, 1H), 7.17-7.21 (m,3H), 5.29 (s, 1H), 3.17 (q, J=6.8 Hz, 2H), 2.56 (t, J=7.6 Hz, 2H), 1.76(quint, J=7.2 Hz, 2H), 1.48-1.61 (m, 4H), 1.39 (s, 3H), 0.90 (t, J=7.6Hz, 3H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-methylhex-1-ynyl)phenyl)propyl)acetamidefollowed by purification by flash chromatography chromatography (72:8:20to 90:10:0 EtOAc/7 M NH₃ in MeOH/hexanes) gave1-(3-(3-aminopropyl)phenyl)-3-methylhex-1-yn-3-ol as a yellow oil. Yield(0.371 g, 76%, two steps): ¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (t, J=8 Hz,1H), 7.14-7.18 (m, 3H), 5.29 (br s, 1H), 2.56 (t, J=7.6 Hz, 2H), 2.47(t, J=7.2 Hz, 2H), 1.41-1.62 (m, 6H), 1.39 (s, 3H), 1.34 (br s, 2H),0.90 (t, J=7.6 Hz, 3H).

Step 3: Hydrogenation of1-(3-(3-aminopropyl)phenyl)-3-methylhex-1-yn-3-ol gave Example 41 as apale yellow oil. Yield (0.260 g, 77%): ¹H NMR (400 MHz, CDCl₃) δ 7.18(t, J=8 Hz, 1H), 6.97-7.02 (m, 3H), 2.71 (t, J=7.2 Hz, 2H), 2.58-2.66(m, 4H), 1.70-1.80 (m, 4H), 1.44-1.52 (m, 2H), 1.35-1.44 (m, 2H),1.26-1.35 (br s, 3H), 1.21 (s, 3H), 0.93 (t, J=7.2 Hz, 3H). ESI MS m/z250.5 [M+H]⁺, 232.4 [M+H−H₂O]⁺.

Example 42 Preparation of1-(3-(3-aminopropyl)phenyl)-3,5-dimethylhexan-3-ol

1-(3-(3-Aminopropyl)phenyl)-3,5-dimethylhexan-3-ol was preparedfollowing the method used in Example 2 and 3.

Step 1: Coupling of 3,5-dimethylhex-1-yn-3-ol with bromide 10 followingthe method described in Example 3 (except that the alkynol was addedafter degassing) gave2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,5-dimethylhex-1-ynyl)phenyl)propyl)acetamideas a brown oil. Yield (0.287 g, 40%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.41(br s, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.16-7.20 (m, 3H), 5.25 (s, 1H),3.16 (q, J=6.8 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.90-1.96 (m, 1H), 1.76(quint, J=7.6 Hz, 2H), 1.53 (m, 2H), 1.42 (s, 3H), 0.96 (d, J=6.8 Hz,6H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,5-dimethylhex-1-ynyl)phenyl)propyl)acetamidefollowing the method of Example 3, except that the reaction mixture wasstirred at room temperature overnight, gave1-(3-(3-aminopropyl)phenyl)-3,5-dimethylhex-1-yn-3-ol as a clear oil.Yield (0.141 g, 72%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.27 (m, 4H),5.25 (s, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.47 (t, J=6.0 Hz, 2H), 1.93(quint, J=6.4 Hz, 1H), 1.60 (q, J=6.8 Hz, 2H), 1.54 (t, J=6.0 Hz, 2H),1.42 (s, 3H), 1.35 (br s, 2H), 0.97 (d, J=6.4 Hz, 6H).

Step 3: Hydrogenation of1-(3-(3-aminopropyl)phenyl)-3,5-dimethylhex-1-yn-3-ol following themethod of Example 2 followed by flash chromatography (5% (7NNH₃/MeOH)/dichloromethane), gave Example 42 as a colorless oil. Yield(0.048 g, 41%): ¹H NMR (400 MHz, CDCl₃) δ 7.18 (t, J=8.0 Hz, 1H),6.97-7.03 (m, 3H), 2.71 (t, J=7.2 Hz, 2H), 2.57-2.68 (m, 4H), 1.70-1.88(m, 5H), 1.36-1.52 (m, 5H), 1.24 (s, 3H), 0.97 (dd, J=6.4, 2.8 Hz, 6H).ESI MS m/z 264.5 [M+H]⁺, 246.5 [M+H−H₂O]⁺.

Example 43 Preparation of1-(3-(3-aminopropyl)phenethyl)-2,2,6,6-tetramethylcyclohexanol

1-(3-(3-Aminopropyl)phenethyl)-2,2,6,6-tetramethylcyclohexanol wasprepared following the method used in Example 2 and 4.

Step 1: Coupling of 1-ethynyl-2,2,6,6-tetramethylcyclohexanol withbromide 10 following the method used in Example 4 gave2,2,2-trifluoro-N-(3-(3-((1-hydroxy-2,2,6,6-tetramethylcyclohexyl)ethynyl)phenyl)propyl)acetamideas a light brown foam. Yield (0.192 g, 84%): ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (br s, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.18-7.23 (m, 3H), 4.92 (s,1H), 3.18 (q, J=6.8 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 1.76 (quint, J=7.6Hz, 2H), 1.22-1.50 (m, 6H), 1.14 (s, 6H), 1.04 (s, 6H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-((1-hydroxy-2,2,6,6-tetramethylcyclohexyl)ethynyl)phenyl)propyl)acetamidewas conducted following the procedure described in Example 4, exceptthat the product was purified by flash chromatography (10% 7 M NH₃ inMeOH-EtOAc), gave1-((3-(3-aminopropyl)-phenyl)ethynyl)-2,2,6,6-tetramethylcyclohexanol asa white solid. Yield (0.016 g, 73%): ¹H NMR (400 MHz, DMSO-d₆) δ7.15-7.27 (m, 4H), 4.92 (s, 1H), 2.57 (t, J=7.2 Hz, 2H), 2.47 (t, J=7.2Hz, 2H), 1.26-1.66 (m, 10H), 1.14 (s, 6H), 1.04 (s, 6H).

Step 3: Hydrogenation of1-((3-(3-aminopropyl)phenyl)ethynyl)-2,2,6,6-tetramethylcyclohexanolfollowing the method used for Example 2 gave Example 43 as a colorlessoil. Yield (0.075 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 7.20 (t, J=8.0 Hz,1H), 6.97-7.06 (m, 3H), 2.60-2.77 (m, 6H), 1.86-1.92 (m, 2H), 1.73-1.82(m, 2H), 1.54-1.69 (m, 3H), 1.49 (br s, 3H), 1.36-1.44 (m, 1H),1.11-1.22 (m, 2H), 1.05 (s, 6H), 1.01 (s, 6H). ESI MS m/z 318.7 [M+H]⁺,300.7 [M+H−H₂O]⁺.

Example 44 Preparation of4-(3-(3-amino-2,2-dimethylpropyl)phenethyl)heptan-4-ol

4-(3-(3-amino-2,2-dimethylpropyl)phenethyl)heptan-4-ol was preparedfollowing the method shown in Scheme 15:

Step 1: An oven-dried flask under argon was charged withisobutyronitrile (2.15 mL, 24.0 mmol) and anhydrous THF (60 mL) andcooled to −78° C. A solution of lithium diisopropylamide (12 mL of a 2.0M solution in heptane/THF/ethylbenzene, 24 mmol) was added in aliquotsover 20 min then the reaction was stirred for 25 min. 3-Bromobenzylbromide (70) (3.98 g, 15.92 mmol) was added and the cold bath wasremoved. After stirring for an additional 2 h, the reaction was quenchedwith the slow addition of water, then EtOAc was added. The aqueous layerwas partly saturated with sodium chloride. The layers were separated,and the aqueous layer was extracted with EtOAc twice. The combinedorganics were washed with water and brine, dried over Na₂SO₄ andconcentrated under reduced pressure to give nitrile 71 as an orange oilwhich later solidified (4.16 g, quant. yield). This material was used inthe next synthetic step without further purification. ¹H NMR (400 MHz,CDCl₃) δ 7.40-7.45 (m, 2H), 7.20-7.25 (m, 2H), 2.78 (s, 2H), 1.36 (s,6H).

Step 2: To an ice-cold mixture of crude3-(3-bromophenyl)-2,2-dimethylpropanenitrile (71) (3.0 g, 12.6 mmol) inanhydrous THF (20 mL) was added BH₃-THF (20 mL of a 1M solution in THF,20 mmol) slowly. The reaction was allowed to warm slowly and stirred for19 h. The reaction was quenched with the dropwise addition of 6 M HClthen stirred for 1.5 h. Volatiles were removed under reduced pressure.The aqueous layer was extracted with diethyl ether twice then EtOAc wasadded and the mixture was made basic with 5 M aqueous KOH. The layerswere separated and the aqueous layer was extracted with EtOAc twice. Thecombined organics were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to give3-(3-bromophenyl)-2,2-dimethylpropan-1-amine as a light yellow oil (2.3g). This material was taken on to the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.35 (m, 1H), 7.30 (t,J=1.7 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 7.06 (dd, J=7.6, 1.2 Hz, 1H),2.50 (s, 2H), 2.47 (s, 2H), 0.84 (s, 6H).

Step 3: Crude 3-(3-bromophenyl)-2,2-dimethylpropan-1-amine (2.3 g) wasdissolved in THF (40 mL). Di-tert-butyl dicarbonate (2.3 g, 10.5 mmol),then triethylamine (2.8 mL, 20.1 mmol) were added and the mixture wasstirred for 1.5 h. The reaction mixture was concentrated under reducedpressure and the product was purified by flash chromatography (0-35%EtOAc-hexanes gradient) to give aryl bromide 72 as a colorless oil.Yield (3.3 g, 77%): ¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J=7.6 Hz, 1H),7.27 (t, J=1.6 Hz, 1H), 7.14 (t, J=7.7 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H),4.58 (br s, 1H), 2.98 (d, J=6.5 Hz, 2H), 2.48 (s, 2H), 1.45 (s, 9H),0.85 (s, 6H).

Step 4: tert-Butyl 3-(3-bromophenyl)-2,2-dimethylpropylcarbamate (72)(3.2 g, 9.35 mmol) was dissolved in EtOAc (55 mL), and a solution ofHCl-EtOAc (˜4.2 M, 20 mL, 84 mmol) was added. The reaction was ventedwith a needle and stirred at room temperature for 2.5 h. The reactionwas then diluted with hexanes and the white solid was collected on afritted glass funnel. The mother liquor was concentrated under reducedpressure, suspended in ˜5-10% EtOAc-hexanes, and the white solid wascollected and combined with the first batch. The solid was dried in avacuum oven at room temperature overnight to give pure3-(3-bromophenyl)-2,2-dimethylpropan-1-amine hydrochloride as a whitesolid. Yield (1.52 g): ¹H NMR (400 MHz, CDCl₃) δ 8.53 (br s, 2H), 7.37(dq, J=1.2 and 8.0 Hz, 1H), 7.31 (t, J=1.6 Hz, 1H), 7.13 (t, J=7.7 Hz,1H), 7.08 (dt, J=8.0, 1.6 Hz, 1H), 2.83-2.84 (m, 2H), 2.67 (s, 2H), 1.09(s, 6H).

Step 5: 3-(3-Bromophenyl)-2,2-dimethylpropan-1-amine hydrochloride (1.52g, 5.45 mmol) was dissolved in anhydrous THF (50 mL). Et₃N (1.5 mL,10.76 mmol) was added slowly to produce a white slurry. Ethyltrifluoroacetate (2 mL, 16.8 mmol) was added and the mixture was stirredat room temp for 15.5 h. Additional ethyl trifluoroacetate (˜0.75 mL,6.2 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added and themixture was stirred for 4 h. The reaction mixture was concentrated underreduced pressure. The product was taken up in EtOAc and the solution waswashed with saturated aqueous NaHCO₃ (2×) and brine, dried over Na₂SO₄and concentrated under reduced pressure to giveN-(3-(3-bromophenyl)-2,2-dimethylpropyl)-2,2,2-trifluoroacetamide (73)as a yellow oil. Yield (1.84 g, 58% yield for two steps): ¹H NMR (400MHz, CDCl₃) δ 7.39 (ddd, J=8.0, 2.0, 0.8 Hz, 1H), 7.29 (t, J=1.6 Hz,1H), 7.17 (t, J=7.6 Hz, 1H), 7.05 (dt, J=7.6, 1.6 Hz, 1H), 6.16 (br s,1H), 3.24 (d, J=6.8 Hz, 2H), 2.53 (s, 2H), 0.93 (s, 6H).

Step 6:N-(3-(3-bromophenyl)-2,2-dimethylpropyl)-2,2,2-trifluoroacetamide (73)(0.489 g, 1.45 mmol) was coupled with 4-ethynylheptan-4-ol (44) (0.28 g,2.0 mmol) following the method described in Example 16 and the productwas purified by flash chromatography (0 to 50% EtOAc-hexanes gradient)to give2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-2,2-dimethylpropyl)acetamide(74) as a yellow oil. Yield (0.350 g, 61%): ¹H NMR (400 MHz, CD₃OD) δ7.20-7.25 (m, 3H), 7.12-7.15 (m, 1H), 3.19 (s, 2H), 2.54 (s, 2H),1.58-1.71 (m, 8H), 0.98 (t, J=7.2 Hz, 6H), 0.85 (s, 6H).

Step 7: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-2,2-dimethylpropyl)acetamide(74) (0.345 g, 0.87 mmol) was conducted following the method describedin Example 2 and the product was purified by flash chromatography (90 to100% EtOAc-hexanes then 10% 3.5 M NH₃ in MeOH-EtOAc) to give alkyne 75as an oil along with recovered starting material. Yield (0.0847 g, 32%yield): ¹H NMR (400 MHz, CD₃OD) δ 7.19-7.24 (m, 3H), 7.11-7.13 (m, 1H),2.53 (s, 2H), 2.44 (s, 2H), 1.56-1.72 (m, 8H), 0.98 (t, J=7.2 Hz, 6H),0.85 (s, 6H).

Step 8: Hydrogenation of alkyne 75 following the method used for Example2 gave Example 44 as a pale yellow oil. Yield (0.077 g, 99%): 1H NMR(400 MHz, DMSO-d₆) δ 7.11 (t, J=7.6 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H),6.88-6.90 (m, 2H), 3.93 (s, 1H), 2.40 (s, 2H), 2.26 (s, 2H), 1.50-1.55(m, 2H), 1.43 (br s, 2H), 1.21-1.34 (m, 8H), 0.83 (t, J=7.0 Hz, 6H),0.71 (s, 6H). ESI MS m/z 306.4 [M+H]

Example 45 Preparation of1-(3-(3-aminopropyl)phenyl)-3,4-dimethylpentan-3-ol

1-(3-(3-Aminopropyl)phenyl)-3,4-dimethylpentan-3-ol was preparedfollowing the method used in Example 2.

Step 1: Coupling of 3,4-dimethylpent-1-yn-3-ol with bromide 10 gave2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,4-dimethylpent-1-ynyl)phenyl)propyl)acetamideas an amber oil. Yield (0.98 g, 89%): ¹H NMR (400 MHz, CD₃OD) δ7.15-7.25 (m, 4H), 3.27-3.31 (m, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.82-1.90(m, 3H), 1.50 (s, 3H), 1.09 (d, J=6.4 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,4-dimethylpent-1-ynyl)phenyl)propyl)acetamidegave 1-(3-(3-aminopropyl)phenyl)-3,4-dimethylpent-1-yn-3-ol as a yellowoil. Yield (0.456 g, 65%): ¹H NMR (400 MHz, CD₃OD) δ 7.15-7.25 (m, 4H),2.60-2.65 (m, 4H), 1.85(quint, J=6.8 Hz, 1H), 1.72-1.79 (m, 2H), 1.47(s, 3H), 1.09 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H).

Step 3: Hydrogenation of1-(3-(3-aminopropyl)phenyl)-3,4-dimethylpent-1-yn-3-ol gave Example 45as a colorless oil. Yield (0.384 g, 84%): ¹H NMR (400 MHz, CDCl₃) δ 7.18(t, J=8.0 Hz, 1H), 6.97-7.03 (m, 3H), 2.71 (t, J=7.2 Hz, 2H), 2.58-2.69(m, 4H), 1.70-1.82 (m, 5H), 1.50 (br s, 3H), 1.14 (s, 3H), 0.93 (dd,J=12.4, 6.8 Hz, 6H). ESI MS m/z 250.5 [M+H]⁺, 232.5 [M+H−H₂O]⁺.

Example 46 Preparation of 4-(3-(3-aminopropyl)phenyl)-2-phenylbutan-2-ol

4-(3-(3-Aminopropyl)phenyl)-2-phenylbutan-2-ol was prepared followingthe method used in Example 2 and 4.

Step 1: Coupling of 2-phenylbut-3-yn-2-ol with bromide 10 gave2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-phenylbut-1-ynyl)phenyl)propyl)acetamideas a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (br s, 1H), 7.62 (m,2H), 7.51 (m, 1H), 7.36 (m, 2H), 7.26 (m, 4H), 6.15 (s, 1H), 3.16 (m,2H), 2.57 (m, 2H), 1.78 (m, 2H), 1.69 (s, 3H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-phenylbut-1-ynyl)phenyl)propyl)acetamidegave 4-(3-(3-aminopropyl)phenyl)-2-phenylbut-3-yn-2-ol as a yellow oil.Yield (0.122 g, 27% for two steps): ¹H NMR (400 MHz, DMSO-d₆) δ7.60-7.63 (m, 1H), 7.33-7.38 (m, 1H), 7.18-7.28 (m, 7H), 6.16 (br s,1H), 2.57 (m, 2H), 2.51 (m, 2H), 1.69 (s, 3H), 1.56-1.63 (m, 2H), 1.34(br s, 2H).

Step 3: Hydrogenation of4-(3-(3-aminopropyl)phenyl)-2-phenylbut-3-yn-2-ol gave Example 46 as acolorless oil. Yield (0.073 g, 71%): ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.42(m, 2H), 7.25-7.31 (m, 2H), 7.14-7.29 (m, 1H), 7.04-7.10 (m, 1H),6.84-6.91 (m, 3H), 2.60 (t, J=7.2 Hz, 2H), 2.46-2.57 (m, 3H), 2.29-2.38(m, 1H), 1.96-2.10 (m, 2H), 1.60-1.80 (m, 5H), 1.51 (s, 3H). ESI MS m/z284.5 [M+H], 266.5 [M+H−H₂O]⁺.

Example 47 Preparation of1-(3-(3-aminopropyl)phenyl)-4-methylpentan-3-ol

1-(3-(3-Aminopropyl)phenyl)-4-methylpentan-3-ol was prepared followingthe method used in Example 2 and 4.

Step 1: Coupling of 4-methylpent-1-yn-3-ol with bromide 10 gave2,2,2-trifluoro-N-(3-(3-(3-hydroxy-4-methylpent-1-ynyl)phenyl)propyl)acetamideas a yellow oil contaminated with alkyne dimer which was used withoutpurification in the next step. ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (br s,1H), 7.18-7.29 (m, 4H), 5.37 (d, J=5.6 Hz, 1H), 4.20 (t, J=5.6 Hz, 1H),3.16 (dt, J=6.8, 6.0 Hz, 2H), 2.56 (t, J=7.6 Hz, 2H), 1.70-1.81 (m, 3H),0.96 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-4-methylpent-1-ynyl)phenyl)propyl)acetamidegave 1-(3-(3-aminopropyl)phenyl)-4-methylpent-1-yn-3-ol as a yellow oil.Yield (10.174 g, 47%, two steps): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15-7.27(m, 4H), 4.29 (d, J=5.6 Hz, 1H), 2.63 (m, 4H), 1.88 (m, 1H), 1.76 (m,2H), 0.96 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H).

Step 3: Hydrogenation of1-(3-(3-aminopropyl)phenyl)-4-methylpent-1-yn-3-ol gave Example 47 as acolorless oil. Yield (0.091 g, 58%): ¹H NMR (400 MHz, CDCl₃) δ 7.18 (t,J=8.0 Hz, 1H), 6.97-7.04 (m, 3H), 3.37 (ddd, J=8.8, 4.8, 3.2 Hz, 1H),2.75-2.85 (m, 1H), 2.71 (t, J=7.2 Hz, 2H), 2.55-2.65 (m, 3H), 1.71-1.82(m, 3H), 1.61-1.71 (m, 2H), 1.52 (br s, 3H), 0.90 (dd, J=1.2, 6.8 Hz,6H). ESI MS m/z 236.4 [M+H]⁺.

Example 48 Preparation of 1-(3-(3-aminopropyl)phenethyl)cyclopentanol

1-(3-(3-Aminopropyl)phenethyl)cyclopentanol was prepared following themethod used in Example 2 and 4.

Step 1: Coupling of 1-ethynylcyclopentanol with bromide 10 gave2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclopentyl)ethynyl)phenyl)propyl)acetamideas a yellow oil which was used without purification in the next step: ¹HNMR (400 MHz, CD₃OD) δ 7.15-7.25 (m, 4H), 3.28 (t, J=7.2 Hz, 2H), 2.62(t, J=7.2 Hz, 2H), 1.97-2.00 (m, 2H), 1.73-1.91 (m, 8H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclopentyl)-ethynyl)phenyl)propyl)acetamidegave 1-((3-(3-aminopropyl)phenyl)ethynyl)cyclopentanol as a yellow oil.Yield (0.478 g, 62% for two steps): ¹H NMR (400 MHz, DMSO-d₆) δ7.14-7.34 (m, 4H), 2.59-2.64 (m, 4H), 1.97-2.00 (m, 4H), 1.71-1.87 (m,6H).

Step 3: Hydrogenation of1-((3-(3-aminopropyl)phenyl)ethynyl)cyclopentanol gave Example 48 as acolorless oil. Yield (0.261 g, 75%): ¹H NMR (400 MHz, CDCl₃) δ 7.19 (t,J=8.0 Hz, 1H), 6.98-7.05 (m, 3H), 2.69-2.76 (m, 4H), 2.62 (t, J=7.6 Hz,2H), 1.85-1.92 (m, 2H), 1.79-1.85 (m, 2H), 1.72-1.79 (m, 2H), 1.56-1.72(m, 6H), 1.37 (br s, 3H). ESI MS m/z 248.5 [M+H]⁺, 230.4 [M+H−H₂O]⁺.

Example 49 Preparation of1-(3-(3-aminopropyl)phenyl)-3,4,4-trimethylpentan-3-ol

1-(3-(3-Aminopropyl)phenyl)-3,4,4-trimethylpentan-3-ol was preparedfollowing the method used in Example 2.

Step 1: Coupling of 3,4,4-trimethylpent-1-yn-3-ol with bromide 10 in a1:1 mixture of DMF and triethylamine gave2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,4,4-trimethylpent-1-ynyl)phenyl)propyl)acetamideas an orange oil. Yield (0.84 g, 73%): ¹H NMR (400 MHz, CD₃OD) δ7.15-7.25 (m, 4H), 3.29 (t, J=7.2 Hz, 2H), 2.61 (t, J=8.0 Hz, 2H), 1.86(quint, J=7.6 Hz, 2H), 1.49 (s, 3H), 1.09 (br s, 9H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,4,4-trimethylpent-1-ynyl)phenyl)propyl)acetamidegave 1-(3-(3-aminopropyl)phenyl)-3,4,4-trimethylpent-1-yn-3-ol as ayellow oil. Yield (0.493 g, 83%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15-7.24(m, 4H), 2.60-2.65 (m, 4H), 1.72-1.79 (m, 2H), 1.49 (s, 3H), 1.09 (s,9H).

Step 3: Hydrogenation of1-(3-(3-aminopropyl)phenyl)-3,4,4-trimethylpent-1-yn-3-ol gave Example49 as a colorless oil. Yield (0.388 g, 82%): ¹H NMR (400 MHz, CDCl₃) δ7.19 (t, J=8.0 Hz, 1H), 6.98-7.05 (m, 3H), 2.70-2.79 (m, 3H), 2.58-2.68(m, 3H), 1.67-1.87 (m, 4H), 1.31 (br s, 3H), 1.21 (s, 3H), 0.94 (s, 9H).ESI MS m/z 264.6 [M+H]+, 246.5 [M+H−H₂O]⁺.

Example 50 Preparation of 1-(3-(2-aminoethoxy)phenyl)-3-ethylpentan-3-ol

1-(3-(2-aminoethoxy)phenyl)-3-ethylpentan-3-ol was prepared followingthe method used in Example 9 except that hydrogenation was conductedbefore deprotection of the amine.

Step 1: Sonogashira coupling of 3-ethylpent-1-yn-3-ol with bromide 19,followed by flash chromatography (5-50% EtOAc/hexanes gradient) gaveN-(2-(3-(3-ethyl-3-hydroxypent-1-ynyl)phenoxy)ethyl)-2,2,2-trifluoroacetamideas an amber oil. Yield (2.1 g, 75%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.58(m, 1H), 7.24 (t, J=8.0 Hz, 1H), 6.88-6.96 (m, 3H), 5.12 (s, 1H), 4.08(t, J=5.6 Hz, 2H), 3.53 (q, J=6.4 Hz, 2H), 1.54-1.65 (m, 4H), 0.96 (t,J=7.6 Hz, 6H).

Step 2: Hydrogenation ofN-(2-(3-(3-ethyl-3-hydroxypent-1-ynyl)phenoxy)ethyl)-2,2,2-trifluoroacetamide,followed by flash chromatography (5-20% EtoAc/hexanes gradient) gaveN-(2-(3-(3-ethyl-3-hydroxypentyl)phenoxy)ethyl)-2,2,2-trifluoroacetamideas a pale yellow waxy solid. Yield (2.06 g, 97%). ¹H NMR (400 MHz,DMSO-d₆) δ 9.59 (m, 1H), 7.14 (t, J=7.6 Hz, 1H), 6.68-6.76 (m, 3H), 4.04(t, J=5.6 Hz, 2H), 3.91 (s, 1H), 3.53 (q, J=5.6 Hz, 2H), 2.45-2.50 (m,2H), 1.49-1.55 (m, 2H), 1.36 (q, J=7.6 Hz, 4H), 0.78 (t, J=7.6 Hz, 6H).

Step 3: Deprotection ofN-(2-(3-(3-ethyl-3-hydroxypentyl)phenoxy)-ethyl)-2,2,2-trifluoroacetamidefollowed by flash chromatography (10% (7N NH₃/MeOH)/dichloromethane)gave Example 50 as a yellow oil. Yield (0.557 g, 38%). ¹H NMR (400 MHz,CDCl₃) δ 7.13 (t, J=7.6 Hz, 1H), 6.64-6.73 (m, 3H), 3.91 (brs, 1H), 3.85(t, J=4.8 Hz, 2H), 2.45-2.49 (m, 2H), 1.50-1.56 (m, 2H), 1.43 (brs, 2H),1.36 (q, J=7.6 Hz, 4H), 0.78 (t, J=7.6 Hz, 6H).

Example 51 Preparation of1-(3-(2-aminoethoxy)phenyl)-3-isopropyl-4-methylpentan-3-ol

1-(3-(2-Aminoethoxy)phenyl)-3-isopropyl-4-methylpentan-3-ol was preparedfollowing the method used in Example 9.

Step 1: Coupling of 3-isopropyl-4-methylpent-1-yn-3-ol with bromide 19following the method described in Example 9 except that the reaction wasrun for 20 h, gave2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-isopropyl-4-methylpent-1-ynyl)phenoxy)ethyl)acetamideas an oil which solidified upon standing. Yield (0.94 g, 46%): ¹H NMR(400 MHz, CDCl₃) δ 7.23 (t, J=8.0 Hz, 1H), 7.07 (dt, J=7.6, 1.0 Hz, 1H),6.95 (dd, J=2.5, 1.4 Hz, 1H), 6.85 (ddd, J=8.4, 2.7, 1.0 Hz, 1H), 6.70(br s, 1H), 4.10 (t, J=5.1 Hz, 2H), 3.79 (dt, J=5.1 Hz, 2H), 2.04 (m,2H), 1.80 (s, 1H), 1.09 (d, J=6.7 Hz, 6H), 1.05 (d, J=6.7 Hz, 6H).

Step 2: Deprotection of2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-isopropyl-4-methylpent-1-ynyl)phenoxy)ethyl)acetamidegave 1-(3-(2-aminoethoxy)phenyl)-3-isopropyl-4-methylpent-1-yn-3-ol as awhite solid. Yield (0.529 g, 76%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (t,J=7.8 Hz, 1H), 6.90-6.95 (m, 2H), 6.87-6.88 (m, 1H), 4.83 (br s, 1H),3.89 (t, J=5.7 Hz, 2H), 2.83 (t, J=5.7 Hz, 2H), 1.86 (m, 2H), 1.47 (brs, 2H), 0.98 (d, J=6.8 Hz, 6H), 0.93 (d, J=6.7 Hz, 6H). ¹³C NMR (100MHz, DMSO-d₆) δ 159.29, 130.48, 124.58, 124.32, 117.46, 115.72, 92.60,84.54, 76.74, 71.04, 41.62, 34.95, 18.98, 17.21. ESI MS m/z 276.39[M+H]⁺, 258.37 [M+H−H₂O]⁺.

Step 3: Hydrogenation of1-(3-(2-aminoethoxy)phenyl)-3-isopropyl-4-methylpent-1-yn-3-ol gaveExample 51 as a colorless oil. Yield (0.238 g, 79%): ¹H NMR (400 MHz,CDCl₃) δ 7.17 (t, J=8.0 Hz, 1H), 6.69-6.80 (m, 3H), 3.96 (t, J=5.2 Hz,2H), 3.06 (t, J=5.2 Hz, 2H), 2.58-2.64 (m, 2H), 1.90-2.02 (m, 2H),1.74-1.80 (m, 2H), 1.43 (br s, 3H), 0.98 (t, J=7.2 Hz, 12H). ESI MS m/z280.6 [M+H]⁺, 262.5 [M+H−H₂O]⁺.

Example 52 Preparation of 5-(3-(2-aminoethoxy)phenethyl)nonan-5-ol

5-(3-(2-Aminoethoxy)phenethyl)nonan-5-ol was prepared following themethod used in Example 9.

Step 1: Coupling of 5-ethynylnonan-5-ol with bromide 19 gaveN-(2-(3-(3-butyl-3-hydroxyhept-1-ynyl)phenoxy)ethyl)-2,2,2-trifluoroacetamide.Yield (1.06 g, 75%): ¹H NMR (400 MHz, CDCl₃) δ 7.23 (t, J=8.0 Hz, 1H),7.06 (dt, J=7.6 and 1.2 Hz, 1H), 6.94 (dd, J=2.5, 1.4 Hz, 1H), 6.86(ddd, J=8.4, 2.7, 1.0 Hz, 1H), 6.72 (br s, 1H), 4.10 (t, J=5.3 Hz, 2H),3.79 (dt, J=5.3 Hz, 2H), 1.96 (s, 1H), 1.70-1.75 (m, 4H), 1.50-1.58 (m,4H), 1.34-1.43 (m, 4H), 0.94 (t, J=7.2 Hz, 6H).

Step 2: Deprotection ofN-(2-(3-(3-butyl-3-hydroxyhept-1-ynyl)-phenoxy)ethyl)-2,2,2-trifluoroacetamidegave 5-((3-(2-aminoethoxy)phenyl)-ethynyl)nonan-5-ol as a colorless oilwhich solidified upon standing. Yield (0.695 g, 92%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.24 (t, J=7.8 Hz, 1H), 6.92-6.93 (m, 1H), 6.90-6.91 (m, 1H),6.85-6.86 (m, 1H), 5.13 (br s, 1H), 3.89 (t, J=5.7 Hz, 2H), 2.83 (t,J=5.7 Hz, 2H), 1.52-1.60 (m, 6H), 1.40-1.49 (m, 4H), 1.25-1.34 (m, 4H),0.88 (t, J=7.2 Hz, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.28, 130.49,124.50, 124.26, 117.35, 115.76, 94.87, 83.08, 71.03, 70.27, 42.19,41.60, 26.85, 23.15, 14.74. ESI MS m/z 304.42 [M+H]⁺, 286.42 [M+H−H₂O]⁺.

Step 3: Hydrogenation of 5-((3-(2-aminoethoxy)phenyl)ethynyl)nonan-5-olgave Example 52 as a colorless oil. Yield (0.154 g, 73%): ¹H NMR (400MHz, CDCl₃) δ 7.18 (t, J=8.0 Hz, 1H), 6.69-6.81 (m, 3H), 3.97 (t, J=5.2Hz, 2H), 3.06 (t, J=5.2 Hz, 2H), 2.56-2.63 (m, 2H), 1.68-1.75 (m, 2H),1.44-1.52 (m, 4H), 1.36-1.42 (br s, 3H), 1.24-1.36 (m, 8H), 0.91 (t,J=6.8 Hz, 6H). ESI MS m/z 308.6 [M+H]⁺, 290.6 [M+H−H₂O]⁺.

Example 53 Preparation of 4-(3-(2-aminoethoxy)phenyl)-2-methylbutan-2-ol

4-(3-(2-Aminoethoxy)phenyl)-2-methylbutan-2-ol was prepared followingthe method used in Example 9.

Step 1: Coupling of 2-methylbut-3-yn-2-ol with bromide 10 following themethod described in Example 9 except that the reaction was run for 19 h,gave2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-methylbut-1-ynyl)phenoxy)ethyl)acetamide.Yield (0.667 g, 70%): ¹H NMR (400 MHz, CDCl₃) δ 7.23 (t, J=7.8 Hz, 1H),7.06 (dt, J=7.6 and 1.2 Hz, 1H), 6.94 (dd, J=2.5, 1.4 Hz, 1H), 6.86(ddd, J=8.2, 2.5, 1.0 Hz, 1H), 6.74 (br s, 1H), 4.09 (t, J=4.9 Hz, 2H),3.80 (dt, J=5.5 Hz, 2H), 2.04 (s, 1H), 1.61 (s, 6H).

Step 2: Deprotection of2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-methylbut-1-ynyl)phenoxy)ethyl)acetamidegave 4-(3-(2-aminoethoxy)phenyl)-2-methylbut-3-yn-2-ol as a white solid.Yield (0.240 g, 52%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.23 (t, J=8.0 Hz,1H), 6.89-6.93 (m, 2H), 6.86-6.88 (m, 1H), 5.43 (br s, 1H), 3.89 (t,J=5.9 Hz, 2H), 2.83 (t, J=5.9 Hz, 2H), 1.45 (br s, 2H), 1.44 (s, 6H).¹³C NMR (100 MHz, DMSO-d₆) δ 159.27, 130.45, 124.38, 124.20, 117.21,116.00, 96.57, 80.99, 71.03, 64.27, 41.59, 32.28. ESI MS m/z 220.31[M+H]⁺, 202.28 [M+H−H₂O]⁺; HPLC (Method A) t_(R)=2.79 min.

Step 3: Hydrogenation of4-(3-(2-aminoethoxy)phenyl)-2-methylbut-3-yn-2-ol gave Example 53 as acolorless oil. Yield (0.143 g, 73%): ¹H NMR (400 MHz, CDCl₃) δ 7.18 (t,J=8.0 Hz, 1H), 6.70-6.82 (m, 3H), 3.97 (t, J=5.2 Hz, 2H), 3.07 (t, J=5.2Hz, 2H), 2.63-2.70 (m, 2H), 1.74-1.81 (m, 2H), 1.47 (s, 3H), 1.27 (s,6H). ESI MS m/z 224.4 [M+H]⁺, 206.3 [M+H−H₂O]⁺.

Example 54 Preparation of 1-(3-(2-aminoethoxy)phenethyl)cyclopentanol

1-(3-(2-Aminoethoxy)phenethyl)cyclopentanol was prepared following themethod used in Example 9.

Step 1: Coupling of 1-ethynylcyclopentanol with bromide 19 following themethod described in Example 9 except that the reaction was run for 19.5h, gave2,2,2-trifluoro-N-(2-(3-((1-hydroxycyclopentyl)ethynyl)phenoxy)ethyl)acetamideas a brown oil. Yield (1.055 g, 92%): ¹H NMR (400 MHz, CDCl₃) δ 7.23 (t,J=8.0 Hz, 1H), 7.06 (dt, J=7.6, 1.2 Hz, 1H), 6.95 (dd, J=2.5, 1.4 Hz,1H), 6.85 (ddd, J=8.4, 2.7, 1.0 Hz, 1H), 6.72 (br s, 1H), 4.09 (t, J=5.3Hz, 2H), 3.78 (dt, J=5.1 Hz, 2H), 2.00-2.09 (m, 4H), 1.76-1.93 (m, 5H).

Step 2: Deprotection of2,2,2-trifluoro-N-(2-(3-((1-hydroxycyclopentyl)ethynyl)phenoxy)ethyl)acetamidegave 1-((3-(2-aminoethoxy)phenyl)ethynyl)cyclopentanol as an oil whichsolidified upon standing. Yield (0.502 g, 66%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.23 (t, J=8.0 Hz, 1H), 6.88-6.94 (m, 3H), 5.28 (br s, 1H),3.89 (t, J=5.7 Hz, 2H), 2.83 (t, J=5.7 Hz, 2H), 1.82-1.89 (m, 4H),1.63-1.74 (m, 4H), 1.48 (br s, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.27,130.45, 124.50, 124.18, 117.20, 115.93, 95.65, 81.97, 73.44, 71.01,42.66, 41.58, 23.75. ESI MS m/z 246.33 [M+H]⁺, 228.30 [M+H−H₂O]+; HPLC(Method A) t_(R)=4.19 min.

Step 3: Hydrogenation of1-((3-(2-aminoethoxy)phenyl)ethynyl)cyclopentanol gave Example 54 as acolorless oil. Yield (0.353 g, 76%): ¹H NMR (400 MHz, CDCl₃) δ 7.16 (t,J=8.0 Hz, 1H), 6.68-6.81 (m, 3H), 3.95 (t, J=5.2 Hz, 2H), 3.04 (t, J=5.2Hz, 2H), 2.72 (m, 2H), 1.86 (m, 2H), 1.72-1.82 (m, 2H), 1.40-1.72 (m,9H). ESI MS m/z 250.4 [M+H]⁺, 232.4 [M+H−H₂O]⁺.

Example 55 Preparation of1-(3-(3-aminopropyl)phenyl)-3-isopropyl-4-methylpentan-3-ol

1-(3-(3-Aminopropyl)phenyl)-3-isopropyl-4-methylpentan-3-ol was preparedfollowing the method used in Example 2 and 13.

Step 1: Coupling of 3-isopropyl-4-methylpent-1-yn-3-ol with bromide 10following the method used in Example 13 gave2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-isopropyl-4-methylpent-1-ynyl)phenyl)propyl)acetamideas a pale yellow oil. Yield (1.375 g, 66%): ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (br s, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.17-7.22 (m, 3H), 4.81 (s,1H), 3.17 (q, J=6.8 Hz, 2H), 2.56 (t, J=8.0 Hz, 2H), 1.86 (quint, J=6.8Hz, 2H), 1.76 (quint, J=7.6 Hz, 2H), 0.99 (d, J=6.8 Hz, 6H), 0.94 (d,J=6.8 Hz, 6H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-isopropyl-4-methylpent-1-ynyl)phenyl)propyl)acetamidefollowing the method used in Example 2 followed by flash chromatography(9:1 CH₂Cl₂: 7 M NH₃ in MeOH) gave1-(3-(3-aminopropyl)phenyl)-3-isopropyl-4-methylpent-1-yn-3-ol as aclear oil. Yield (0.835 g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15-7.26(m, 4H), 4.82 (br s, 1H), 2.56 (t, J=7.6 Hz, 2H), 2.47-2.52 (m, 2H),1.86 (quint, J=6.8 Hz, 2H), 1.59 (quint, J=6.8 Hz, 2H), 1.56 (br.s, 2H),1.05 (d, J=6.8 Hz, 6H), 1.03 (d, J=6.8 Hz, 6H).

Step 3: Hydrogenation of1-(3-(3-aminopropyl)phenyl)-3-isopropyl-4-methylpent-1-yn-3-ol followingthe method used in Example 2 gave Example 55 as a colorless oil. Yield(0.538 g, 68%): ¹H NMR (400 MHz, CDCl₃) δ 7.19 (t, J=8.0 Hz, 1H),6.97-7.60 (m, 3H), 2.73 (t, J=7.2 Hz, 2H), 2.58-2.65 (m, 4H), 1.92-2.04(m, 2H), 1.72-1.82 (m, 4H), 1.30-1.40 (br s, 3H), 0.99 (t, J=7.2 Hz,12H). ESI MS m/z 278.6 [M+H]⁺, 260.5 [M+H−H₂O]⁺.

Example 56 Preparation of4-(3-(3-aminopropyl)phenethyl)-2,6-dimethylheptan-4-ol

4-(3-(3-Aminopropyl)phenethyl)-2,6-dimethylheptan-4-ol was preparedfollowing the method used in Example 55.

Step 1: Coupling of 4-ethynyl-2,6-dimethylheptan-4-ol with bromide 10gave2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-isobutyl-5-methylhex-1-ynyl)phenyl)propyl)acetamideas a pale yellow oil. Yield (1.25 g, 63%): ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (br s, 1H), 7.14-7.28 (m, 4H), 5.02 (s, 1H), 3.17 (q, J=6.8 Hz,2H), 2.56 (t, J=7.6 Hz, 2H), 1.93-1.99 (m, 2H), 1.75 (quint, J=7.6 Hz,2H), 1.47-1.56 (m, 4H), 0.86-0.98 (m, 12H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-isobutyl-5-methylhex-1-ynyl)phenyl)propyl)acetamidegave 4-((3-(3-aminopropyl)phenyl)ethynyl)-2,6-dimethylheptan-4-ol as aclear oil. Yield (0.73 g, 77%): ¹H NMR (400 MHz, DMSO-d₆) 7.22-7.26 (m,1H), 7.12-7.18 (m, 3H), 5.04 (br s, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.50(t, J=6.8 Hz, 2H), 1.91-2.01 (m, 2H), 1.47-1.62 (m, 6H), 0.98 (m, 6H),0.96 (m, 6H).

Step 3: Hydrogenation of4-((3-(3-aminopropyl)phenyl)ethynyl)-2,6-dimethylheptan-4-ol gaveExample 56 as a colorless oil. Yield (0.559 g, 77%): ¹H NMR (400 MHz,CDCl₃) δ 7.18 (t, J=8.0 Hz, 1H), 6.97-7.03 (m, 3H), 2.73 (t, J=7.2 Hz,2H), 2.56-2.65 (m, 4H), 1.72-1.88 (m, 6H), 1.40-1.48 (m, 7H), 0.98 (dd,J=6.8, 4.8 Hz, 12H). ESI MS m/z 306.7 [M+H]⁺, 288.6 [M+H−H₂O]⁺.

Example 57 Preparation of 5-(3-(3-aminopropyl)phenyl)pentan-2-ol

5-(3-(3-Aminopropyl)phenyl)pentan-2-ol was prepared following the methodused in Examples 2, 13, and 23.

Step 1: Coupling of pent-4-yn-2-ol with bromide 10 following the methodused in Example 13 except the reaction was conducted at room temperaturegave2,2,2-trifluoro-N-(3-(3-(4-hydroxypent-1-ynyl)phenyl)propyl)acetamide asa pale yellow oil. Yield (0.95 g, 63%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40(br s, 1H), 7.14-7.26 (m, 4H), 4.80 (s, 1H), 3.81 (q, J=5.6 Hz, 1H),3.16 (q, J=6.8 Hz, 2H), 2.54 (t, J=5.6 Hz, 2H), 2.39 (dd, J=16.8, 6.8Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.17 (d, J=5.6 Hz, 3H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-(4-hydroxypent-1-ynyl)phenyl)propyl)acetamidefollowing the method described in Example 23 gave5-(3-(3-aminopropyl)phenyl)pent-4-yn-2-ol as a clear oil Yield (0.34 g,94%): ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.25 (m, 1H), 7.23 (t, J=1.6 Hz,1H), 7.20 (ddd, J=7.4, 7.4, 0.6 Hz, 1H), 7.11 (dt, J=7.2, 1.6 Hz, 1H),4.04 (dq, J=12.5, 6.3 Hz, 1H), 2.72 (t, J=6.9 Hz, 2H), 2.51-2.64 (m,4H), 1.72-1.79 (m, 2H), 1.65 (br s, 3H), 1.32 (d, J=6.3 Hz, 3H).

Step 3: Hydrogenation of 5-(3-(3-aminopropyl)phenyl)pent-4-yn-2-olfollowing the method used in Example 2 gave Example 57 as a colorlessoil. Yield (0.173 g, 64%): ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.22 (m, 1H),6.97-7.04 (m, 3H), 3.80 (quint., J=6.4 Hz, 1H), 2.72 (t, J=7.2 Hz, 2H),2.55-2.65 (m, 4H), 1.57-1.82 (m, 4H), 1.52 (br s, 3H), 1.40-1.54 (m,2H), 1.17 (d, J=6.0 Hz, 3H). ESI MS m/z 222.5 [M+H]⁺.

Example 58 Preparation of 3-(3-(2-methoxyphenethyl)phenyl)propan-1-amine

3-(3-(2-Methoxyphenethyl)phenyl)propan-1-amine was prepared followingthe method used in Examples 22 except that the hydrogenation wasconducted before the deprotection of the amine.

Step 1: Sonogashira reaction of bromide 57 with 2-ethynylanisole wasconducted by the method used in Example 22 except that diisopropylaminewas used in place of triethylamine and the reaction mixture was heatedat reflux. tert-Butyl3-(3-((2-methoxyphenyl)ethynyl)phenyl)propylcarbamate was obtained as ayellow oil. Yield (0.42 g, 72%): MS: 366 [M+1]⁺.

Step 2: Reduction of tert-butyl 3-(3-((2-methoxyphenyl)ethynyl)phenyl)propylcarbamate gave tert-butyl3-(3-(2-methoxyphenethyl)phenyl)propylcarbamate as an off-white solid.Yield (0.242 g, 85%): MS: 370 [M+1].

Step 3: Deprotection of tert-butyl 3-(3-(2-methoxyphenethyl)phenyl)propylcarbamate gave Example 58 as yellow oil. Yield (0.192 g, 78%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.17-7.23 (m, 2H), 7.11 (d, J=7.6 Hz, 1H),7.0-7.07 (m, 3H), 6.96 (d, J=8.4 Hz, 1H), 6.82-6.86 (m, 1H), 3.79 (s,3H), 2.74-2.84 (m, 6H), 2.62 (t, J=7.6 Hz, 2H), 1.77-1.86 (m, 2H). ¹³CNMR (100 MHz, DMSO-d₆): 157.5, 142.4, 141.2, 130.0, 129.8, 128.8, 128.7,127.8, 126.5, 126.2, 120.6, 111.1, 55.8, 38.8, 35.9, 32.3, 32.2, 29.2.MS: 270 [M+1]⁺.

Example 59 Preparation of6-(3-(3-amino-1-hydroxypropyl)phenyl)hexan-1-ol

6-(3-(3-Amino-1-hydroxypropyl)phenyl)hexan-1-ol was prepared followingthe method used in Example 17.

Step 1: Coupling of hex-5-yn-1-ol with bromide 39 gave tert-butyl3-hydroxy-3-(3-(6-hydroxyhex-1-ynyl)phenyl)propylcarbamate as a brownoil. Yield (0.405 g, 77%).

Step 2: Deprotection of tert-butyl3-hydroxy-3-(3-(6-hydroxyhex-1-ynyl)phenyl)propylcarbamate followed bypurification by preparative HPLC (Method 2P) gave6-(3-(3-Amino-1-hydroxypropyl)phenyl)hex-5-yn-1-ol hydrochloride as awhite solid. Yield (0.12 g, 32%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (brs, 2H), 7.25-7.35 (m, 4H), 5.51 (br s, 1H), 4.68 (dd, J=7.8, 4.4 Hz,1H), 4.46 (t, J=6.4 Hz, 1H), 3.40-3.44 (m, 2H), 2.77-2.88 (m, 2H),2.41-2.44 (m, 2H), 1.80-1.93 (m, 2H), 1.56-1.62 (m, 4H).

Step 3: Hydrogenation of6-(3-(3-amino-1-hydroxypropyl)phenyl)hex-5-yn-1-ol hydrochloridefollowing the method used in Example 13 followed by purification bypreperative HPLC (Method 1P) gave Example 59 trifluoroacetate as a whitesolid. Yield (21 mg, 14%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (br s, 3H),7.23 (t, J=7.5 Hz, 1H), 7.12 (s, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.06 (d,J=7.5 Hz, 1H), 5.49 (br s, 1H), 4.63 (t, J=6.3 Hz, 1H), 4.31 (t, J=4.9Hz, 1H), 3.35 (dd, J=11.1, 6.1 Hz, 2H), 2.78-2.90 (m, 2H), 2.54 (t,J=7.7, 2H), 1.78-1.84 (m, 2H), 1.50-1.58 (m, 2H), 1.27-1.40 (m, 6H).

Example 60 Preparation of4-(3-(3-amino-1-hydroxypropyl)phenyl)butan-1-ol

4-(3-(3-Amino-1-hydroxypropyl)phenyl)butan-1-ol was prepared followingthe method used in Example 19 except that the amine deprotection wasconducted before the hydrogenation.

Step 1: Sonogashira reaction of bromide 19 with but-3-yn-1-ol gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-hydroxybut-1-ynyl)phenyl)propyl)acetamideas brown oil. Yield (0.908 g, 90%): ¹H NMR (400 MHz, CDCl₃) δ 7.41 (s,1H), 7.23-7.36 (m, 3H), 4.84-4.87 (m, 1H), 3.81 (t, J=6.4 Hz, 2H),3.66-3.69 (m, 1H), 3.39-3.42 (m, 1H), 2.69 (t, J=6.4 Hz, 2H), 1.93-1.99(m, 2H).

Step 2: A mixture of,2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-hydroxybut-1-ynyl)phenyl)propyl)acetamide,potassium carbonate (1.6 g, 11.5 mmol) and water (3 mL) in MeOH (15 mL)was heated under reflux for 4 h. Reaction mass was concentrated todryness under reduced pressure to give4-(3-(3-amino-1-hydroxypropyl)phenyl)but-3-yn-1-ol as pale yellow oilafter purification by flash chromatography with 15% MeOH—NH₃(9.5:0.5)-DCM. Yield (0.38 g, 60%). This compound was utilized as suchfor the next transformation.

Step 3: A solution of 4-(3-(3-amino-1-hydroxypropyl)phenyl)but-3-yn-1-ol(5) in 2-PrOH (10 mL) was degassed and purged with nitrogen. To this wasadded Pd on C (0.08 g, 10%). The flask was evacuated and filled withhydrogen. After repeating this procedure thrice, the reaction mixturewas stirred under H₂ balloon at RT. After about 72 h, this mixture wasfiltered through Celite and concentrated under reduced pressure to yieldyellow oil. The crude product was purified by flash chromatography(0-15% MeOH—NH₃ (9.5:0.5)-DCM gradient) to obtain Example 60 as yellowoil. Yield (0.14 g, 37%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.19 (t, J=7.6,1H), 7.13 (s, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H),4.60-4.63 (m, 1H), 4.36 (bs, 1H), 3.39 (t, J=7.6 Hz, 2H), 2.58-2.68 (m,2H), 2.55 (t, J=7.6 Hz, 2H), 1.55-1.68 (m, 4H), 1.44-1.46 (m, 2H). ¹³CNMR (100 MHz, DMSO-d₆) δ 146.0, 141.8, 127.7, 126.4, 125.6, 123.0, 71.4,60.5, 42.4, 38.9, 35.1, 32.1, 27.5. MS: 224 [M+1]⁺.

Example 61 Preparation of3-amino-1-(3-(2-methoxyphenethyl)phenyl)propan-1-ol

3-Amino-1-(3-(2-methoxyphenethyl)phenyl)propan-1-ol was preparedfollowing the method used in Example 19.

Step 1: Sonogashira reaction of bromide 43 with1-ethynyl-2-methoxybenzene gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-((2-methoxyphenyl)ethynyl)phenyl)propyl)acetamideas brown oil. Yield (1.12 g, 96%): ¹H NMR (400 MHz, CDCl₃) δ 7.55 (s,1H), 7.50 (d, J=5.6 Hz, 2H), 7.28-7.37 (m, 3H), 6.90-6.96 (m, 2H),4.84-4.87 (m, 1H), 3.92 (s, 3H), 3.66-3.69 (m, 1H), 3.39-3.42 (m, 1H),2.32 (bs, 1H), 1.93-1.99 (m, 2H).

Step 2: Reduction of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((2-methoxyphenyl)ethynyl)phenyl)propyl)acetamide gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-methoxyphenethyl)phenyl)propyl)acetamideas yellow oil. Yield (1.1 g, crude): ¹H NMR (400 MHz, CDCl₃) δ 7.36 (bs,1H), 7.24-7.30 (m, 1H), 7.13-7.20 (m, 3H), 7.08 (s, 1H), 7.04 (d, J=1.6Hz, 7.2 Hz, 1H), 6.82-6.87 (m, 2H), 4.83-4.86 (m, 1H), 3.81 (s, 3H),3.61-3.66 (m, 1H), 3.36-3.42 (m, 1H), 2.17 (bs, 1H), 1.93-1.99 (m, 2H).This compound was utilized as such for the next transformation.

Step 3: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-methoxyphenethyl)-phenyl)propyl)acetamidegave a dark oil, which upon purification by flash chromatography (0-10%MeOH—NH₃ (9.5:0.5)-DCM gradient) yielded Example 61 as pale green oil.Yield (0.616 g, 75%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.04-7.23 (m, 6H),6.94 (d, J=8.0 Hz, 1H), 6.82 (t, J=7.2 Hz, 1H), 4.59 (t, J=6.4 Hz, 1H),3.75 (s, 3H), 2.78 (s, 4H), 2.66-2.73 (m, 2H), 1.70-1.75 (m, 2H). ¹³CNMR (100 MHz, DMSO-d₆) δ 157.1, 145.7, 141.6, 129.6, 129.3, 128.0,127.3, 126.7, 125.5, 123.1, 120.2, 110.6, 70.5, 55.3, 37.6, 35.6, 31.8.MS: 286 [M+1]⁺.

Example 62 Preparation of3-(3-(2-(thiophen-2-yl)ethyl)phenyl)propan-1-amine

3-(3-(2-(Thiophen-2-yl)ethyl)phenyl)propan-1-amine was preparedfollowing the method used in Example 31.

Step 1: Alkyne 61 was coupled with 2-bromothiophene and purified byflash chromatography (15% EtOAc-hexanes) to give2-(3-(3-(thiophen-2-ylethynyl)phenyl)propyl)isoindoline-1,3-dione as ayellow solid. Yield (0.490 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.84 (dd,J=5.6, 3.2 Hz, 2H), 7.71 (dd, J=5.2, 3.2 Hz, 2H), 7.35 (s, 1H),7.26-7.30 (m, 3H), 7.23 (t, J=7.6 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.01(dd, J=5.2, 3.6 Hz, 1H), 3.76 (t, J=7.2 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H),2.05 (quint., J=7.6 Hz, 2H).

Step 2:2-(3-(3-(Thiophen-2-ylethynyl)phenyl)propyl)isoindoline-1,3-dione wasdeprotected and the reaction mixture diluted with diethyl ether and theprecipitate removed by filtration. The filtrate was concentrated underreduced pressure and the diethyl ether precipitation step was repeated.Purification by preperative HPLC (Method 1P) gave3-(3-(thiophen-3-ylethynyl)phenyl)propan-1-amine trifluoroacetate as acream-colored solid. Yield (0.210 g, 65%): ¹H NMR (400 MHz, CDCl₃) δ7.94 (br s, 3H), 7.33 (d, J=7.6 Hz, 1H), 7.25-7.28 (m, 2H), 7.22 (d,J=7.6 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 6.99 (dd, J=5.2, 3.6 Hz, 1H),2.89 (t, J=7.2 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.92-1.99 (m, 2H).

Step 3: Hydrogenation followed by purification by preperative HPLC(Method 1P) gave Example 62 trifluoroacetate as a off-white solid. Yield(170 mg, 29%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (br s, 3H), 7.28 (d,J=5.0 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 7.06 (s,1H), 7.01 (d, J=7.6 Hz, 1H), 6.90 (dd, J=5.0, 3.4 Hz, 1H), 6.82 (d,J=3.4 Hz, 1H), 3.08 (t, J=7.8 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.71-2.79(m, 2H), 2.58 (t, J=7.7 Hz, 2H), 1.79 (quint, J=7.7 Hz, 2H).

Example 63 Preparation of 3-amino-1-(3-(4-phenylbutyl)phenyl)propan-1-ol

3-Amino-1-(3-(4-phenylbutyl)phenyl)propan-1-ol was prepared followingthe method used in Example 19 except that the amine deprotection wasconducted before the hydrogenation.

Step 1: Coupling of aryl bromide 43 with but-3-ynylbenzene following themethod used in Example 19 and purification by flash chromatography (20%EtOAc-hexanes) gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-phenylbut-1-ynyl)phenyl)propyl)acetamideas a brown oil. Yield (0.340 g, 52%): ¹H NMR (400 MHz, CDCl₃) δ7.28-7.36 (m, 7H), 7.24-7.27 (m, 2H), 4.84-4.88 (m, 1H), 3.66-3.74 (m,1H), 3.41 (ddd, J=17.6, 8.0, 4.4 Hz, 1H), 2.93 (t, J=7.6 Hz, 2H), 2.70(t, J=7.6 Hz, 2H), 2.27 (d, J=1.6 Hz, 1H), 1.90-2.03 (m, 2H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-phenylbut-1-ynyl)phenyl)propyl)acetamidewas conducted following the method used in Example 19, except that thereaction was heated overnight. Purification by prep HPLC (method 004P)gave 3-amino-1-(3-(4-phenylbut-1-ynyl)phenyl)propan-1-ol as a brownsolid. Yield (0.085 g, 33%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.21-7.34 (m,9H), 4.67 (t, J=6.0 Hz, 1H), 2.88 (t, J=7.2 Hz, 2H), 2.68-2.74 (m, 4H),1.68 (q, J=6.4 Hz, 2H), 0.86-0.92 (m, 1H).

Step 3: Reduction of 3-amino-1-(3-(4-phenylbutyl)phenyl)propan-1-ol (6)in 2-PrOH at RT for 14 h gave a yellow oil after work-up. The crudeproduct was purified by flash chromatography (0-15% MeOH—NH₃(9.5:0.5)-DCM gradient). This was then dissolved in 2-PrOH (10 mL) andstirred for an hour with HCl in Dioxane (1 mL, 4M). The mixture wasconcentrated to dryness under reduced pressure. Purification by flashchromatography (0-15% MeOH-DCM gradient) gave Example 63 as whitesemi-solid. Yield (0.13 g, 19%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.20-7.26(m, 3H), 7.09-7.15 (m, 5H), 7.05 (d, J=7.2 Hz, 1H), 4.60 (t, J=7.2 Hz,1H), 2.78-2.88 (m, 2H), 2.55 (m, 4H), 1.78-1.84 (m, 2H), 1.53-1.55 (m,4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 145.3, 142.2, 142.0, 128.3, 128.1,126.9, 125.6, 125.5, 123.0, 69.7, 36.7, 36.4, 35.0, 34.9, 30.7. MS: 284[M+1]⁺.

Example 64 Preparation of 2-(3-(4-methylpentyl)phenoxy)ethanamine

2-(3-(4-Methylpentyl)phenoxy)ethanamine was prepared following themethod used in Example 9 except that the hydrogenation was conductedbefore the deprotection of the amine.

Step 1: Sonogashira reaction of bromide 19 with 4-methyl-1-pentyne gave2,2,2-trifluoro-N-(2-(3-(4-methylpent-1-ynyl)phenoxy)ethyl) acetamide asa brown oil. Yield (0.955 g, 63%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22-7.27(m, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.90-6.94 (m, 2H), 4.10 (t, J=5.6 Hz,2H), 3.53-3.57 (m, 2H), 2.31 (d, J=6.4 Hz, 2H), 1.80-1.90 (m, 1H), 1.0(d, J=6.8 Hz, 6H).

Step 2: The reduction of2,2,2-trifluoro-N-(2-(3-(4-methylpent-1-ynyl)phenoxy)ethyl)acetamideafforded 2,2,2-trifluoro-N-(2-(3-(4-methylpentyl)phenoxy)ethyl)acetamide as yellow oil. Yield (0.815 g, 85%): ¹H NMR (400MHz, DMSO-d₆) δ 7.21-7.25 (m, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.70-6.73 (m,2H), 4.10 (t, J=5.0 Hz, 2H), 3.76-3.80 (m, 2H), 2.56 (t, J=7.8 Hz, 2H),1.53-1.64 (m, 2H), 1.30-1.38 (m, 3H), 0.87 (d, J=6.4 Hz, 6H).

Step 3: Deprotection of5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pentanamide gave Example64 as yellow oil. Yield (0.415 g, 73%): ¹H NMR (400 MHz, DMSO-d₆) δ7.19-7.23 (m, 1H), 6.77-6.82 (m, 3H), 4.11 (t, J=5.2 Hz, 2H), 3.16 (t,J=5.2 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 1.50-1.60 (m, 3H), 1.14-1.20 (m,2H), 0.85 (d, J=6.8 Hz, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ 157.9, 144.1,129.3, 121.2, 114.6, 111.8, 64.6, 38.5, 38.0, 35.4, 28.7, 27.3, 22.5.MS: 222 [M+1]⁺.

Example 65 Preparation of 2-(3-(3-phenylprop-1-ynyl)phenoxy)ethanamine

2-(3-(3-Phenylpropyl)phenoxy)ethanamine was prepared following themethod used in Example 9.

Step 1: Sonogashira reaction of bromide 19 with 3-phenyl-1-propyne gave2,2,2-trifluoro-N-(2-(3-(3-phenylprop-1-ynyl)phenoxy)ethyl) acetamide asa brown oil. Yield (1.1 g, crude). The crude material was directlyutilized for further deprotection reaction.

Step 2: Deprotection of2,2,2-trifluoro-N-(2-(3-(3-phenylprop-1-ynyl)phenoxy)ethyl)acetamidegave 2-(3-(3-phenylprop-1-ynyl)phenoxy)ethanamine as brown oil. Yield(0.74 g, 94%). The crude material was directly utilized for furtherreduction reaction.

Step 3: The reduction of 2-(3-(3-phenylprop-1-ynyl)phenoxy)ethanamineafforded Example 65 as brown oil. Yield (0.078 g, 23%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.26-7.30 (m, 2H), 7.17-7.25 (m, 4H), 6.77-6.83 (m, 3H), 4.09(t, J=5.2 Hz, 2H), 3.15 (t, J=5.2 Hz, 2H), 2.56-2.60 (m, 4H), 1.82-1.90(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.5, 144.1, 142.3, 129.8, 128.8,128.7, 126.2, 121.7, 115.1, 112.4, 65.2, 39.1, 35.2, 33.0. MS: 256[M+1]⁺.

Example 66 Preparation of 4-(3-(2-aminoethoxy)phenyl)butan-1-ol

4-(3-(2-Aminoethoxy)phenyl)butan-1-ol was prepared following the methodused in Example 64.

Step 1: Sonogashira reaction of bromide 19 with but-3-yn-1-ol gave2,2,2-trifluoro-N-(2-(3-(4-hydroxybut-1-ynyl)phenoxy)ethyl)acetamide asa brown oil. Yield (0.9 g, 93%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.21-7.25(m, 1H), 7.06 (d, J 7.6 Hz, 1H), 6.94 (bs, 1H), 6.85 (dd, J=8.4, 2.4 Hz,1H), 4.09 (t, J=5.0 Hz, 2H), 3.76-3.85 (m, 4H), 2.70 (t, J=6.4 Hz, 2H).

Step 2: The reduction of 2,2,2-trifluoro-N-(2-(3-(4-hydroxybut-1-ynyl)phenoxy)ethyl)acetamide afforded2,2,2-trifluoro-N-(2-(3-(4-hydroxybutyl) phenoxy) ethyl)acetamide asyellow oil. Yield (0.42 g, 63%). MS: 304 [M−1].

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-(4-hydroxybutyl)phenoxy)ethyl)acetamide gave Example 66 as yellow oil. Yield (0.121 g, 44%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.14-7.18 (m, 1H), 6.71-6.76 (m, 3H), 3.88 (t,J=5.8 Hz, 2H), 3.39 (t, J=6.6 Hz, 2H), 2.85 (t, J=5.8 Hz, 2H), 2.53 (t,J=6.8 Hz, 2H), 1.53-1.60 (m, 2H), 1.38-1.45 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 159.1, 144.4, 129.6, 121.0, 115.0, 112.0, 70.4, 61.0, 41.4,35.5, 32.6, 27.8. MS: 210 [M+1]⁺.

Example 67 Preparation of 2-(3-phenethylphenoxy)ethanamine ol

2-(3-Phenethylphenoxy)ethanamine was prepared following the method usedin Example 64.

Step 1: Sonogashira reaction of bromide 19 with ethynylbenzene gave2,2,2-trifluoro-N-(2-(3-(phenylethynyl)phenoxy)ethyl)acetamide as brownoil. Yield (0.755 g, 70%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.65 (bs, 1H),7.53-7.57 (m, 2H), 7.41-7.47 (m, 3H), 7.34-7.36 (m, 1H), 7.15 (d, J=7.6Hz, 1H), 7.12 (s, 1H), 7.0 (dd, J=7.6, 2.0 Hz, 1H), 4.14 (t, J=5.4 Hz,2H), 3.55-3.60 (m, 2H).

Step 2: The reduction of2,2,2-trifluoro-N-(2-(3-(phenylethynyl)phenoxy)ethyl)acetamide afforded2,2,2-trifluoro-N-(2-(3-phenethylphenoxy)ethyl)acetamide as yellow oil.Yield (0.61 g, 80%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (bs, 1H),7.15-7.21 (m, 4H), 7.15-7.20 (m, 2H), 6.80-6.83 (m, 2H), 6.75 (d, J=7.6Hz, 1H), 4.06 (t, J=5.6 Hz, 2H), 3.54-3.60 (m, 2H), 2.81-2.90 (m, 4H).

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-phenethylphenoxy)ethyl)acetamide gave Example 67 as off-white solid. Yield (0.205 g, 41%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.14-7.28 (m, 6H), 6.83-6.85 (m, 2H), 6.79 (d,J=8.4 Hz, 1H), 4.11 (t, J=5.0 Hz, 2H), 3.18 (t, J=5.0 Hz, 2H), 2.83-2.87(m, 4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 157.8, 143.2, 141.4, 129.3, 128.3,128.2, 125.8, 121.3, 114.7, 112.1, 64.6, 38.2, 37.0, 36.9. MS: 242[M+1]⁺.

Example 68 Preparation of 2-(3-(4-phenylbutyl)phenoxy)ethanamine

2-(3-(4-Phenylbutyl)phenoxy)ethanamine was prepared following the methodused in Example 9.

Step 1: Sonogashira reaction of bromide 19 with but-3-ynyl-benzene gave2,2,2-trifluoro-N-(2-(3-(4-phenylbut-1-ynyl)phenoxy)ethyl)acetamide as aclear oil. Yield (2.8 g, crude). The crude material was directlyutilized for further deprotection reaction.

Step 2: Deprotection of2,2,2-trifluoro-N-(2-(3-(4-phenylbut-1-ynyl)phenoxy)ethyl)acetamide gave2-(3-(4-phenylbut-1-ynyl)phenoxy)ethanamine as yellow oil. Yield (0.700g, 35%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.29-7.33 (m, 4H), 7.20-7.26 (m,2H), 6.88-6.93 (m, 2H), 6.84-6.87 (m, 1H), 3.89 (t, J=5.6, 2H),2.80-2.88 (m, 4H), 2.69 (t, J=7.2, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ158.5, 140.5, 129.7, 128.6, 128.2, 126.2, 124.2, 123.5, 116.6, 114.9,90.0, 81.1, 70.3, 40.9, 34.3, 20.9. MS: 266 [M+1]⁺.

Step 8: The reduction of 2-(3-(4-Phenylbut-1-ynyl)phenoxy)ethanamineafforded Example 68 as yellow oil. Yield (0.178 g, 89%): ¹H NMR (400MHz, DMSO-d₆) δ 7.12-7.27 (m, 6H), 6.76-6.80 (m, 3H), 4.09 (t, J=5.0 Hz,2H), 3.15 (t, J=5.0 Hz, 2H), 2.49-2.57 (m, 4H), 1.53-1.58 (m, 4H). ¹³CNMR (100 MHz, DMSO-d₆) δ 157.9, 143.9, 142.1, 129.3, 128.3, 128.2,125.6, 121.2, 114.6, 111.8, 64.5, 38.5, 34.9, 30.6, 30.5. MS: 270[M+1]⁺.

Example 69 Preparation of 2-(3-(2-methoxyphenethyl)phenoxy)ethanamine

2-(3-(2-Methoxyphenethyl)phenoxy)ethanamine amine was prepared followingthe method used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with 2-ethynyl-anisole gave2,2,2-trifluoro-N-(2-(3-((2-methoxyphenyl)ethynyl)phenoxy)ethyl)acetamide as a brown oil. Yield (0.4 g, 62%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.48 (dd, J=7.6, 1.6 Hz, 1H), 7.37-7.42 (m, 1H), 7.31-7.36(m, 1H), 7.09-7.12 (m, 2H), 7.08 (s, 1H), 6.95-7.01 (m, 2H), 4.13 (t,J=5.6 Hz, 2H), 3.86 (s, 3H), 3.55-3.60 (m, 2H).

Step 2: The reduction of 2,2,2-trifluoro-N-(2-(3-((2-methoxyphenyl)ethynyl)phenoxy) ethyl)acetamide afforded2,2,2-trifluoro-N-(2-(3-(2-methoxyphenethyl) phenoxy)ethyl)acetamide asyellow oil. Yield (0.253 g, 63%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15-7.20(m, 2H), 7.12 (d, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.73-6.86 (m,4H), 4.06 (t, J=5.6 Hz, 2H), 3.79 (s, 3H), 3.56 (t, J=5.4 Hz, 2H),2.75-2.83 (m, 4H).

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-(2-methoxyphenethyl)phenoxy)ethyl)acetamide gave Example 69 as yellow oil. Yield (0.122 g,66%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.16-7.20 (m, 2H), 7.12 (d, J=7.2 Hz,1H), 6.95 (d, J=8.0 Hz, 1H), 6.82-6.86 (m, 1H), 6.74-6.79 (m, 3H), 3.92(t, J=5.6 Hz, 2H), 3.79 (s, 3H), 2.92 (t, J=5.6 Hz, 2H), 2.76-2.84 (m,4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.8, 157.5, 144.0, 130.0, 129.7,129.6, 127.7, 121.3, 120.6, 115.0, 112.3, 111.1, 68.1, 55.8, 40.6, 35.9,32.0. MS: 272 [M+1]⁺.

Example 70 Preparation of(S)-4-(3-(3-amino-1-hydroxypropyl)phenethyl)heptan-4-ol

(S)-4-(3-(3-Amino-1-hydroxypropyl)phenethyl)heptan-4-ol was preparedfollowing the method shown in Scheme 16.

Step 1: To a solution of hydroxyamine 38 (37.61 g, 163.4 mmol) in CH₂Cl₂(250 mL) was added ethyl trifluoroacetate (28 mL, 209.6 mmol) and thereaction mixture was stirred at room temperature for 1 h. After thatCelite (70 g) was added followed by pyridinium chlorochromate (75.65 g,350.9 mmol) and CH₂Cl₂ (200 mL). The reaction mixture was stirred atroom temperature for 18 hrs, the solvent was removed under reducedpressure to give a brown solid which was transferred in a glass filterand washed extensively with MTBE:Hexanes (1:1). The filtrate wasconcentrated under reduced pressure and the residue was crystallizedfrom hexanes:EtOAc (95:5) to give ketone 76 as a white solid. Yield(26.52 g, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (br. t, 1H), 8.06 (t,J=1.8 Hz, 1H), 7.91-7.95 (m, 1H), 7.80-7.85 (m, 1H), 7.48 (t, J=8.0 Hz,1H), 3.50 (q, J=6.5 Hz, 2H), 3.30 (t, J=6.5 Hz, 2H).

Step 2: Coupling of 4-ethynylheptan-4-ol (44) with bromide 76 wasconducted following the method used to prepare Example 2 except that thereaction was stirred at +80 OC for 3 hrs. Purification by flashchromatography (10% to 70% EtOAc-hexanes gradient) gave alkyne 77 as adark yellow oil. Yield (3.15 g, quant.). ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (br. t, 1H), 7.84-7.92 (m, 2H), 7.58-7.63 (m, 1H), 7.50 (t, J=7.6Hz, 1H), 5.19 (s, 1H), 3.51 (q, J=5.7 Hz, 2H), 3.30 (t, J=6.7 Hz, 2H),1.40-1.64 (m, 8H), 0.90 (t, J=7.2 Hz, 6H).

Step 3: Preparation of (+)-diisopinocampheylchloroborane ((+)-Ipc₂B—Cl)solution: To an ice-cold solution of (+)-α-pinene (26.38 g, 193.6 mmol)in hexanes (18 mL) under argon was added monochloroborane-methyl sulfidecomplex (9.5 mL, 91.12 mmol) over 5 min. The mixture was stirred for 5min then allowed to warm to room temperature. The reaction mixture washeated at 30° C. for 3 h. The resulting solution was approximately 1.67M.

To a 0° C. solution of ketone 77 (14.34 g, 37.4 mmol) and diisopropylethylamine (6.5 mL, 37.31 mmol) in anhydrous THF (60 mL) under argon wasadded a solution of (+)-Ipc₂B—Cl (55 mL of the 1.67 M solution preparedabove, 91.12 mmol). The reaction mixture was stirred at 0° C. over 5min, and then at room temperature for 3.5 hrs. The reaction mixture wascooled again to 0° C. and a saturated aqueous NaHCO₃ (80 mL) wascarefully added. The reaction mixture was stirred at 0° C. for 1 h andthen placed to −20 OC overnight. The layers were separated, aqueouslayer was extracted with MTBE, combined organic layers were washed withNaHCO₃, then brine, and then concentrated under reduced pressure.Purification by flash chromatography (10% to 100% EtOAc-hexanesgradient) gave (S)-alkyne 78 as a yellowish oil. Yield (10.55 g, 70%).¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (br. s, 1H), 7.30-7.33 (m, 1H),7.26-7.29 (m, 2H), 7.19-7.23 (m, 1H), 5.36 (br. s, 1H), 5.12 (s, 1H),4.56 (dd, J=4.7, 7.6 Hz, 1H), 3.15-3.27 (m, 2H), 1.70-1.82 (m, 2H),1.40-1.61 (m, 8H), 0.91 (t, J=7.2 Hz, 6H).

Step 4. (S)-Alkyne 78 was hydrogenated by the method used in Example 13except that the reaction was run at room temperature for 2 hrs.Purification by flash chromatography (20% to 80% EtOAc-hexanes gradient)gave alkane 79 as a yellow oil. (Yield 5.13 g, 98%). ¹H NMR (400 MHz,DMSO-d₆) δ 9.32 (br. s, 1H), 7.18 (t, J=7.4 Hz, 1H), 7.06-7.12 (m, 2H),6.99-7.03 (m, 1H), 5.25 (d, J=4.3 Hz, 1H), 4.52 (q, J=4.7 Hz, 1H), 3.95(s, 1H), 3.23 (q, J=7.0 Hz, 2H), 2.48-2.53 (m, 2H), 1.72-1.80 (m, 2H),1.50-1.56 (m, 2H), 1.20-1.36 (m, 8H), 0.84 (t, J=6.9 Hz, 6H).

Step 5. Deprotection of trifluoroacetamide 79 was conducted followingthe method used to prepare Example 9 except that 3 equivalents of K₂CO₃were used and the reaction was stirred at +40 OC for 4 hrs. Purificationby flash chromatography (50% to 100% of 20^(%) 7M NH₃ inMeOH/EtOAc-hexane gradient) gave Example 70 as a light yellow oil. Yield(3.18 g, 82%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (t, J=7.6 Hz, 1H),7.04-7.12 (m, 2H), 6.96-7.00 (m, 1H), 4.59 (dd, J=5.3, 7.4 Hz, 1H), 3.95(s, 1H), 2.54-2.66 (m, 2H), 2.48-2.52 (m, 2H), 1.50-1.64 (m, 4H),1.20-1.35 (m, 8H), 0.84 (t, J=7.0 Hz, 6H). Chiral HPLC 95.3% (AUC),t_(R)=22.2 min.

Example 71 Preparation of(R)-4-(3-(3-amino-1-hydroxypropyl)phenethyl)heptan-4-ol

(R)-4-(3-(3-Amino-1-hydroxypropyl)phenethyl)heptan-4-ol was preparedfollowing the method used in Example 70.

Step 1. Reduction of ketone 77 with (−)-Ipc₂B—Cl gave(R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propyl)acetamideas a colorless oil. Yield (9.53 g, 69%); ¹H NMR (400 MHz, DMSO-d₆) δ9.32 (br. s, 1H), 7.30-7.33 (m, 1H), 7.26-7.29 (m, 2H), 7.19-7.23 (m,1H), 5.36 (br. s, 1H), 5.12 (s, 1H), 4.56 (dd, J=4.7, 7.6 Hz, 1H),3.15-3.27 (m, 2H), 1.70-1.82 (m, 2H), 1.40-1.61 (m, 8H), 0.91 (t, J=7.2Hz, 6H).

Step 2. Hydrogenation of(R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propyl)acetamidegave(R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propyl)acetamideas a light-yellow oil. Yield (4.81 g, 94%). ¹H NMR (400 MHz, DMSO-d₆) δ9.32 (br. s, 1H), 7.18 (t, J=7.4 Hz, 1H), 7.06-7.12 (m, 2H), 6.99-7.03(m, 1H), 5.25 (d, J=4.3 Hz, 1H), 4.52 (q, J=4.7 Hz, 1H), 3.95 (s, 1H),3.23 (q, J=7.0 Hz, 2H), 2.48-2.53 (m, 2H), 1.72-1.80 (m, 2H), 1.50-1.56(m, 2H), 1.20-1.36 (m, 8H), 0.84 (t, J=6.9 Hz, 6H).

Step 3. Deprotection of(R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propyl)acetamidegave Example 71 as yellow oil. Yield (2.87 g, 79%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.16 (t, J=7.6 Hz, 1H), 7.04-7.12 (m, 2H), 6.96-7.00 (m, 1H),4.59 (dd, J=5.3, 7.4 Hz, 1H), 3.95 (s, 1H), 2.54-2.66 (m, 2H), 2.44-2.66(m, 2H), 1.50-1.64 (m, 4H), 1.20-1.35 (m, 8H), 0.84 (t, J=7.0 Hz, 6H).RP-HPLC (Method 2) t_(R)=6.21 min, 96.5% (AUC); ESI MS m/z 294.51[M+H+]⁺. Chiral HPLC 95.1% (AUC), t_(R)=16.6 min

Example 72 Preparation of3-amino-1-(3-(3-methoxypropyl)phenyl)propan-1-ol

3-Amino-1-(3-(3-methoxypropyl)phenyl)propan-1-ol was prepared followingthe method used in Example 19.

Step 1: Sonogashira reaction of 43 with methyl propargyl ether gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-methoxyprop-1-ynyl)phenyl)propyl)acetamideas brown oil. Yield (0.401 g, 82%): ¹H NMR (400 MHz, CDCl₃) δ 7.51 (s,1H), 7.38-7.44 (m, 1H), 7.31-7.35 (m, 2H), 4.84-4.88 (m, 1H), 4.32 (s,2H), 3.66-3.69 (m, 1H), 3.44 (s, 3H), 3.39-3.42 (m, 1H), 2.37 (bs, 1H),1.94-1.99 (m, 2H).

Step 2: Reduction of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-methoxyprop-1-ynyl)phenyl)propyl)acetamideyielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-methoxypropyl)phenyl)propyl)acetamideas yellow oil. Yield (0.298 g, 73%). ¹H NMR (400 MHz, CDCl₃) δ 7.31 (s,1H), 7.13-7.24 (m, 3H), 4.84-4.88 (m, 1H), 3.66-3.70 (m, 1H), 3.49 (m,1H), 3.38 (t, J=6.4 Hz, 2H), 3.34 (s, 3H), 2.69 (t, J=7.6 Hz, 2H),1.90-1.95 (m, 2H), 1.86-1.89 (m, 2H).

Step 3: Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-methoxypropyl)phenyl)propyl)acetamide gave a yellow gel which upon purificationby flash chromatography (0-10% MeOH—NH₃ (9.5:0.5)-DCM gradient) yieldedExample 72 as yellow semi-solid. Yield (0.597 g, 82%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.22 (t, J=7.6 Hz, 1H), 7.13 (s, 1H), 7.11 (d, J=7.6 Hz, 1H),7.04 (d, J=7.6 Hz, 1H), 4.61 (t, J=6.4 Hz, 1H), 3.29 (t, J=6.4 Hz, 2H),3.21 (s, 3H), 2.72-2.77 (m, 2H), 2.58 (t, J=7.2 Hz, 2H), 1.66-1.79 (m,4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 146.1, 142.0, 128.5, 127.3, 126.0,123.5, 71.6, 70.8, 58.3, 38.7, 37.7, 32.2, 31.4. MS: 224 [M+1].

Example 73 Preparation of 3-amino-1-(3-hexylphenyl)propan-1-ol

3-Amino-1-(3-hexylphenyl)propan-1-ol was prepared following the methodused in Example 19.

Step 1: Sonogashira reaction of 43 with 1-hexyne gave2,2,2-trifluoro-N-(3-(3-(hex-1-ynyl)phenyl)-3-hydroxypropyl)acetamide asyellow oil. Yield (1.53 g, 76%): ¹H NMR (400 MHz, CDCl₃) δ 7.38 (s, 1H),7.25-7.34 (m, 3H), 4.88 (m, 1H), 3.65-3.73 (m, 1H), 3.38-3.42 (m, 1H),2.40 (t, J=7.2 Hz, 2H), 2.25 (d, J=2.0, 1H) 1.93-1.99 (m, 2H), 1.45-1.61(m, 4H), 0.94 (t, J=7.2 Hz, 3H).

Step 2: A solution of2,2,2-trifluoro-N-(3-(3-(hex-1-ynyl)phenyl)-3-hydroxypropyl)acetamide inEtOAc (20 mL) was degassed and purged with nitrogen. To this was addedPd on C (0.2 g, 10%). The flask was evacuated and filled with hydrogen.After repeating this procedure thrice, the reaction mixture was stirredunder H₂ balloon for 14 h following which this mixture was filteredthrough a Celite bed and concentrated under reduced pressure to obtain2,2,2-trifluoro-N-(3-(3-hexylphenyl)-3-hydroxypropyl)acetamide as yellowoil. Yield (0.93 g, 75%): ¹H NMR (400 MHz, CDCl₃) δ 7.40 (bs, 1H),7.28-7.31 (m, 2H), 7.12-7.16 (m, 2H), 4.86-4.88 (m, 1H), 3.66-3.71 (m,1H), 3.40-3.43 (m, 1H), 2.58 (t, J=7.6 Hz, 2H), 1.96-1.99 (m, 2H),1.56-1.60 (m. 4H), 1.30-1.35 (m, 4H), 0.88 (t, J=6.8 Hz, 3H).

Step 3: A mixture of2,2,2-trifluoro-N-(3-(3-hexylphenyl)-3-hydroxypropyl)acetamide,potassium carbonate (1.55 g, 11.2 mmol) and water (4 mL) in 2-PrOH (20mL) was heated under reflux for overnight. The reaction mass wasconcentrated to dryness under reduced pressure to yield a yellow oil.This crude product was dissolved in methanol (5 mL) and to it was addedHCl in Dioxane (1 mL, 4M). The mixture stirred for about 30 min afterwhich it was concentrated to dryness under reduced pressure.Purification by flash chromatography (0-10% MeOH-DCM gradient) gaveExample 73 hydrochloride as pale yellow semi-solid. Yield (0.174 g,21%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.67 (bs, 3H), 7.23 (t, J=7.2 Hz, 1H),7.11 (m, 2H), 7.07 (d, J=7.2 Hz, 1H), 4.62-4.65 (m, 1H), 2.78-2.87 (m,2H), 2.49 (m, 2H), 1.80-1.84 (m, 2H), 1.54 (m, 2H), 1.27 (m, 6H), 0.85(t, J=6.8, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 145.3, 142.2, 128.1, 126.9,125.5, 122.9, 69.7, 36.7, 36.4, 35.3, 31.1, 31.0, 28.4, 22.1. MS: 236[M+1]⁺.

Example 74 Preparation of 2-(3-(2-cyclopropylethyl)phenoxy)ethanamine

2-(3-(2-Cyclopropylethyl)phenoxy)ethanamine was prepared following themethod used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with cyclopropyl acetylenegaveN-(2-(3-(2-cyclopropylethynyl)phenoxy)ethyl)-2,2,2-trifluoroacetamide asa clear oil. Yield (2.0 g, 71%): The crude material was directlyhydrogenated.

Step 2: The reduction ofN-(2-(3-(cyclopropylethynyl)phenoxy)ethyl)-2,2,2-trifluoroacetamide gaveN-(2-(3-(2-cyclopropylethyl)phenoxy)ethyl)-2,2,2-trifluoroacetamide asyellow oil. Yield (0.205 g, 45%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (bs,1H), 7.14-7.19 (m, 1H), 6.72-6.80 (m, 3H), 4.06 (t, J=5.6 Hz, 2H),3.53-3.58 (m, 2H), 2.62 (t, J=7.8 Hz, 2H), 1.42-1.48 (m, 2H), 0.62-0.70(m, 1H), 0.37-0.40 (m, 2H), 0.02-0.10 (m, 2H). MS: 300 [M−1].

Step 3: Deprotection ofN-(2-(3-(2-cyclopropylethyl)phenoxy)ethyl)-2,2,2-trifluoroacetamide gaveExample 74 as green oil. Yield (0.121 g, 87%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.13-7.19 (m, 1H), 6.71-6.77 (m, 3H), 3.88 (t, J=5.8 Hz, 2H), 2.85 (t,J=5.8 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 1.43-1.50 (m, 2H), 0.64-0.72 (m,1H), 0.47-0.50 (m, 2H), 0.02-0.06 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ158.6, 143.7, 129.1, 120.5, 114.5, 111.6, 69.8, 40.9, 36.0, 35.4, 10.6,4.4. MS: 206 [M+1]⁺.

Example 75 Preparation of 5-(3-(2-aminoethoxy)phenyl)pentan-1-ol

5-(3-(2-Aminoethoxy)phenyl)pentan-1-ol was prepared following the methodused in Example 64.

Step 1: A mixture of bromide 19 (2.5 g, 8 mmol), pentyn-1-ol (1.34 g, 16mmol) in triethylamine (6 mL, 60 mmol) and DMF (18 mL) was purged withnitrogen for 10 minutes. This was followed by the addition ofPdCl2(PPh₃)₂ (0.28 g, 0.4 mmol), P(o-Tol)₃ (0.122 g, 0.4 mmol) and CuI(0.076 g, 0.4 mmol) and the flask was purged once again with nitrogenand the resulting mixture was heated at 90° C. overnight. This was thenpoured into water, extracted with ethyl acetate. The organic layer waswashed with water, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by flashchromatography (0 to 30% EtOAc-hexanes gradient) gave2,2,2-trifluoro-N-(2-(3-(5-hydroxypent-1-ynyl)phenoxy)ethyl)acetamide asyellow oil. Yield (1.61 g, 63%): ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.24 (m,1H), 7.03 (d, J=7.6 Hz, 1H), 6.91 (dd, J=0.8, 1.2 Hz, 1H), 6.83 (dd,J=5.6, 2.0 Hz, 1H), 6.76 (bs, 1H), 4.06-4.10 (m, 2H), 3.76-3.84 (m, 4H),2.53 (t, J=7.2 Hz, 2H), 1.82-1.90 (m, 2H).

Step 2: Reduction of2,2,2-trifluoro-N-(2-(3-(5-hydroxypent-1-ynyl)phenoxy)ethyl)acetamideafforded 2,2,2-trifluoro-N-(2-(3-(5-hydroxypentyl)phenoxy)ethyl)acetamide as yellow oil. Yield (0.513 g, 72%): ¹H NMR (400MHz, DMSO-d₆) δ 7.15-7.20 (m, 1H), 6.72-6.78 (m, 3H), 4.34 (t, J=5.0 Hz,2H), 4.06 (t, J=5.6 Hz, 2H), 3.52-3.59 (m, 2H), 3.37 (t, J=6.4 Hz, 2H),1.51-1.60 (m, 2H), 1.40-1.47 (m, 2H), 1.24-1.32 (m, 2H). MS: 318 [M−1].

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-(5-hydroxypentyl)phenoxy)ethyl)acetamide gave Example 75 as yellow oil. Yield (0.175 g,49%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.19 (m, 1H), 6.71-6.76 (m, 3H),3.94 (t, J=5.6 Hz, 2H), 3.34 (t, J=6.6 Hz, 2H), 2.90 (t, J=5.6 Hz, 2H),2.50 (t, J=8.0 Hz, 2H), 1.48-1.56 (m, 2H), 1.36-1.46 (m, 2H), 1.22-1.30(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.5, 144.0, 129.2, 120.7, 114.6,111.6, 68.4, 60.7, 40.3, 35.3, 32.4, 30.8, 25.2. MS: 224 [M+1]⁺.

Example 76 Preparation of 3-(3-(2-cyclopropylethyl)phenyl-propan-1-amine

3-(3-(2-Cyclopropylethyl)phenyl-propan-1-amine was prepared followingthe method used for Examples 13 and 22 except that the hydrogenation wasconducted before the deprotection of the amine.

Step 1: To a degassed solution of tert-butyl3-(3-bromophenyl)propylcarbamate (57) (1.0 g, 3.1 mmol) and cyclopropylacetylene (2.9 mL, 3.4 mmol, 70% soln in toluene) in diisopropylamine (4mL) was added PdCl₂(PPh₃)₂ (0.120 g, 0.17 mmol), tri-o-tolylphosphine(0.048 g, 0.16 mmol) and CuI (0.026 g, 0.16 mmol). The resulting mixturewas degassed and stirred under nitrogen at 90° C. for overnight. Themixture was cooled to room temperature and concentrated under reducedpressure. The residue was partitioned between water and ethyl acetate.

The organic layer was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification by flashchromatography (10-40% ethyl acetate-hexane gradient) gave tert-butyl3-(3-(cyclopropylethynyl)phenyl)propylcarbamate. Yield (0.756 g, 79%).This alkyne was used for deprotection without further purification.

Step 2: Reduction of tert-butyl 3-(3-(cyclopropylethynyl)phenyl)propylcarbamate following the method used in Example 22 gave tert-butyl3-(3-(2-cyclopropylethyl)phenyl)propylcarbamate as yellow oil. Yield(0.404 g, 98%): MS: 304 [M+1]⁺.

Step 3: BOC deprotection of tert-butyl 3-(3-(2-cyclopropylethyl)phenyl)propylcarbamate following the method used in Example 13 gave Example 76as yellow oil. Yield (0.19 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ7.17-7.21 (m, 1H), 6.99-7.04 (m, 3H), 2.72 (t, J=7.2 Hz, 2H), 2.58-2.66(m, 4H), 1.75-1.83 (m, 2H), 1.42-1.48 (m, 2H), 0.64-0.71 (m, 1H),0.36-0.41 (m, 2H), 0.01-0.06 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆): 142.7,141.1, 128.8, 128.7, 126.5, 126.0, 38.8, 36.6, 35.8, 32.3, 29.3, 11.1,4.9. MS: 204 [M+1]⁺.

Example 77 Preparation of 2-(3-hexylphenoxy)ethanamine

2-(3-Hexylphenoxy)ethanamine was prepared following the method used inExample 9.

Step 1: Sonogashira reaction of bromide 19 with 1-hexyne gave2,2,2-trifluoro-N-(2-(3-(hex-1-ynyl)phenoxy)ethyl)acetamide as a clearoil. Yield (1.8 g, 72%): ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.23 (m, 1H),7.05 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 6.80 (dd, J=8.0, 2.4 Hz, 1H), 4.10(t, J=5.2 Hz, 2H), 3.77-3.80 (m, 2H), 2.40 (t, J=7.2 Hz, 2H), 1.53-1.61(m, 2H), 1.43-1.50 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

Step 2: Deprotection of2,2,2-trifluoro-N-(2-(3-(hex-1-ynyl)phenoxy)-ethyl)acetamide gave2-(3-(hex-1-ynyl)phenoxy)ethanamine as yellow oil. Yield (0.620 g, 90%):¹H NMR (400 MHz, DMSO-d₆) δ 7.20-7.25 (m, 1H), 6.87-6.93 (m, 3H), 3.91(t, J=5.2 Hz, 2H), 2.79-2.87 (m, 2H), 2.38 (t, J=6.4 Hz, 2H), 1.42-1.53(m, 2H), 1.30-1.40 (m, 2H), 0.88 (t, J=7.2 Hz, 3H). ¹³C NMR (100 MHz,DMSO-d₆) δ 158.9, 130.1, 124.8, 124.1, 117.2, 115.3, 90.9, 80.9, 70.3,41.1, 30.7, 21.9, 18.7, 13.9. ESI MS m/z 218 [M+1]⁺.

Step 3: The reduction of 2-(3-hex-1-ynyl-phenoxy)-ethanamine affordedExample 77 as yellow oil. Yield (0.154 g, 57%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.70-6.75 (m, 3H), 3.91 (t, J=5.6 Hz, 2H),2.86 (t, J=5.6 Hz, 2H), 1.20-1.28 (m, 6H), 1.52 (t, J=7 Hz, 2H), 0.82(t, J=6.6 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.1, 144.4, 129.6,121.0, 114.9, 112.0, 69.9, 35.7, 31.6, 31.3, 28.8, 22.5, 14.6. MS: 222[M+1]⁺.

Example 78 Preparation of 2-(3-(3-methoxypropyl)phenoxy)ethanamine

2-(3-(3-Methoxypropyl)phenoxy)ethanamine was prepared following themethod used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with 3-methoxy-propyne gave2,2,2-trifluoro-N-(2-(3-(3-methoxyprop-1-ynyl)phenoxy)ethyl)acetamide asa clear oil. Yield (0.51 g, 21%): ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.27(m, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 6.88 (dd, J=6.8, 1.6 Hz,1H), 6.71 (bs, 1H), 4.32 (s, 2H), 4.10 (t, J=5.2 Hz, 2H), 3.77-3.82 (m,2H), 3.45 (s, 3H).

Step 2: The reduction of2,2,2-trifluoro-N-(2-(3-(3-methoxyprop-1-ynyl)phenoxy)ethyl)acetamideafforded 2,2,2-trifluoro-N-(2-(3-(3-methoxypropyl)phenoxy)ethyl)acetamide as yellow oil. Yield (0.355 g, 76%). ¹H NMR (400MHz, DMSO-d₆) δ 7.16-7.22 (m, 1H), 6.74-6.79 (m, 3H), 4.07 (t, J=5.6 Hz,2H), 3.54-3.58 (m, 2H), 3.33 (s, 3H), 3.28 (t, J=6.2 Hz, 2H), 2.57 (t,J=7.8 Hz, 2H), 1.73-1.81 (m, 2H).

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-(3-methoxypropyl)phenoxy)ethyl)acetamide gave Example 78 as yellow oil. Yield (0.125 g,52%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (bs, 2H), 7.20-7.24 (m, 1H),6.78-6.83 (m, 3H), 4.14 (t, J=5.6 Hz, 2H), 2.94 (t, J=5.6 Hz, 2H), 2.53(t, J=7.2 Hz, 2H), 2.05 (t, J=7.2 Hz, 2H), 1.44-1.54 (m, 4H). ¹³C NMR(100 MHz, DMSO-d₆) δ 158.4, 144.0, 129.8, 121.7, 115.1, 112.4, 71.6,64.6, 58.3, 38.8, 32.2, 31.2. MS: 210 [M+1]⁺.

Example 79 Preparation of3-amino-1-(3-(3-hydroxypropyl)phenyl)propan-1-ol

3-Amino-1-(3-(3-hydroxypropyl)phenyl)propan-1-ol was prepared followingthe method used in Example 17 except that the hydrogenation wasconducted before the deprotection of the amine.

Step 1: Sonogashira reaction of bromide 39 with propargyl alcohol gavetert-butyl 3-hydroxy-3-(3-(3-hydroxyprop-1-ynyl)phenyl)propylcarbamateas brown oil. Yield (0.880 g, 94%): ¹H NMR (400 MHz, CDCl₃) δ 7.45 (s,1H), 7.28-7.36 (m, 3H), 4.85-4.87 (bs, 1H), 4.70-4.72 (m, 1H), 4.49 (d,J=5.2 Hz, 2H), 3.47-3.50 (m, 1H), 3.44 (bs, 1H), 3.12-3.17 (m, 1H),1.93-1.99 (m, 2H), 1.45 (s, 9H).

Step 2: Reduction reaction of tert-butyl3-hydroxy-3-(3-(3-hydroxyprop-1-ynyl)phenyl)propylcarbamate gavetert-butyl 3-hydroxy-3-(3-(3-hydroxypropyl)phenyl)propylcarbamate asyellow oil. Yield (0.731 g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.20 (t,J=7.6 Hz, 1H), 7.13 (s, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.04 (d, J=7.6 Hz,1H), 6.77 (t, J=5.2 Hz, 1H) 5.15 (d, J=4.4 Hz, 1H), 4.51 (m, 1H), 4.46(t, J=4.4 Hz, 1H), 3.32-3.44 (m, 2H), 2.94-2.98 (m, 2H), 2.58 (t, J=7.6Hz, 2H), 1.64-1.73 (m, 4H), 1.45 (s, 9H).

Step 3: Deprotection of tert-butyl3-hydroxy-3-(3-(3-hydroxypropyl)phenyl) propylcarbamate resulted in thehydrochloride salt. The crude product was subjected to flashchromatography (0-15% MeOH—NH₃ (9.5:0.5)-DCM gradient) to obtain Example79 as pale yellow semi-solid. Yield (0.364 g, 61%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.20 (t, J=7.6 Hz, 1H), 7.10 (s, 1H), 7.07 (d, J=7.6 Hz, 1H),7.02 (d, J=7.6 Hz, 1H), 4.56 (t, J=6.8 Hz, 1H), 3.38 (t, J=6.4 Hz, 2H),2.62-2.64 (m, 2H), 2.54-2.56 (m, 2H), 1.53-1.72 (m, 4H). ¹³C NMR (100MHz, DMSO-d₆) δ 145.7, 142.5, 128.5, 127.4, 126.0, 123.4, 70.1, 60.5,37.1, 36.8, 34.8, 32.2. MS: 210 [M+1]⁺.

Example 80 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenyl)hexan-3-ol

1-(3-(3-Amino-1-hydroxypropyl)phenyl)hexan-3-ol was prepared followingthe method used in Example 19.

Step 1: Sonogashira reaction of 43 (3 g, 9.2 mmol) with hex-1-yn-3-olyielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxyhex-1-ynyl)phenyl)propyl)acetamide as yellow oil. Yield (2.31 g, 73%): ¹H NMR (400 MHz, CDCl₃) δ7.42 (s, 1H), 7.26-7.38 (m, 3H), 4.86 (m, 1H), 4.61 (dd, J=2.0, 5.6 Hz,1H), 3.67-3.71 (m, 1H), 3.37-3.46 (m, 1H), 2.38 (d, J=2.0 Hz, 1H),1.95-1.99 (m, 2H), 1.75-1.88 (m, 2H), 1.53-1.57 (m, 2H), 0.97 (t, J=7.2Hz, 3H).

Step 2: Reduction reaction of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxyhex-1-ynyl)phenyl)propyl)acetamideyielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxyhexyl)phenyl)propyl)acetamideas yellow oil. Yield (0.911 g, 83%). This compound was utilized as suchfor the next transformation.

Step 3: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxyhexyl)phenyl)propyl)acetamideand purification by flash chromatography (0-10% MeOH—NH₃ (9.5:0.5)-DCMgradient) gave Example 80 as yellow oil (the HCl salt was not preparedin this case). Yield (0.325 g, 49%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.23(t, J=7.2 Hz, 1H), 7.17 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.01 (d, J=7.2Hz, 1H), 4.61 (t, J=6.0 Hz, 1H), 4.39 (bs, 1H), 2.55-2.70 (m, 4H),1.53-1.65 (m, 4H), 1.26-1.39 (m, 4H), 0.85 (t, J=6.4 Hz, 3H). ¹³C NMR(100 MHz, DMSO-d₆) δ 146.4, 142.1, 127.8, 126.4, 125.6, 122.9, 71.3,68.7, 42.3, 38.9, 31.6, 18.4, 14.1. MS: 252 [M+1]⁺.

Example 81 Preparation of 1-(3-(2-aminoethoxy)phenyl)hexan-3-ol

1-(3-(2-Aminoethoxy)phenyl)hexan-3-ol was prepared following the methodused in Example 9.

Step 1: Sonogashira reaction of bromide 19 with 4-methyl-pent-1-yn-3-olgave2,2,2-trifluoro-N-(2-(3-(3-hydroxyhex-1-ynyl)phenoxy)ethyl)acetamide asa clear oil. Yield (3 g, crude): The crude material was directlyutilized for further deprotection reaction.

Step 2: Deprotection of2,2,2-trifluoro-N-(2-(3-(3-hydroxyhex-1-ynyl)phenoxy)ethyl)acetamidegave 1-(3-(2-aminoethoxy)phenyl)hex-1-yn-3-ol as a yellow oil. Yield(1.858 g, 88%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.23-7.29 (m, 1H), 6.90-6.98(m, 3H), 4.42 (t, J=6.4 Hz, 2H), 3.92 (t, J=4.8 Hz, 2H), 2.86 (bs, 2H),1.56-1.68 (m, 2H), 1.40-1.49 (m, 2H), 0.91 (t, J=7.6 Hz, 3H). ¹³C NMR(100 MHz, DMSO-d₆) δ 159.0, 130.3, 124.0, 117.1, 115.8, 92.8, 833, 70.4,61.0, 41.2, 40.1, 18.6, 14.2. ESI MS m/z 234 [M+1]⁺.

Step 3: The reduction of 1-(3-(2-aminoethoxy)phenyl)hex-1-yn-3-olafforded Example 81 as yellow oil. Yield (0.55 g, 68%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.71-6.76 (m, 3H), 4.36-4.42 (m, 1H), 3.91(t, J=5.6 Hz, 2H), 2.87 (t, J=5.6 Hz, 2H), 2.62-2.70 (m, 2H), 1.50-1.64(m, 2H), 1.24-1.40 (m, 4H), 0.85 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ158.6, 144.2, 129.2, 120.5, 114.5, 111.5, 69.5, 68.7, 40.8, 39.3, 39.0,31.6, 18.4, 14.1. MS: 238 [M+1]⁺

Example 82 Preparation of3-amino-1-(3-(4-methoxybutyl)phenyl)propan-1-ol

3-Amino-1-(3-(4-methoxybutyl)phenyl)propan-1-ol was prepared followingthe method used in Example 19.

Step 1: Sonogashira reaction of 43 with 4-methoxybut-1-yne gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-methoxybut-1-ynyl)phenyl)propyl)acetamideas brown oil. Yield (0.351 g, 81%): ¹H NMR (400 MHz, CDCl₃) δ 7.40 (s,1H), 7.27-7.37 (m, 3H), 4.83-4.85 (m, 1H), 3.68-3.71 (m, 1H), 3.63 (t,J=6.8 Hz, 2H), 3.39 (s, 3H), 3.34-3.38 (m, 1H), 2.69 (t, J=6.8 Hz, 2H),2.38 (bs, 1H), 1.91-2.02 (m, 2H).

Step 2: Reduction of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-methoxybut-1-ynyl)phenyl)propyl)acetamideyielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-methoxybutyl)phenyl)propyl)acetamideas yellow oil. Yield (0.332 g, 94%).

This compound was utilized as such for the next transformation. MS: 334[M+1]⁺.

Step 3: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-methoxybutyl)phenyl)propyl)acetamideand subsequent purification by flash chromatography (0-10% (MeOH—NH₃(9.5:0.5))-DCM) gave Example 82 as pale green oil. Yield (0.156 g, 61%):¹H NMR (400 MHz, DMSO-d₆) δ 7.20 (t, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.09(d, J=7.6 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 4.58-4.61 (m, 1H), 3.30 (t,J=6.4 Hz, 2H), 3.18 (s, 3H), 2.61 (t, J=6.8 Hz, 2H), 2.58 (t, J=7.2 Hz,2H), 1.63-1.69 (m, 2H), 1.45-1.56 (m, 4H). ¹³C NMR (100 MHz, DMSO-d₆) δ146.6, 142.2, 128.3, 127.0, 126.0, 123.5, 72.2, 71.4, 58.3, 41.4, 38.7,35.5, 29.1, 28.1. MS: 238 [M+1].

Example 83 Preparation of(S)-1-(3-(1-aminopropan-2-yloxy)phenethyl)cyclohexanol

(S)-1-(3-(1-Aminopropan-2-yloxy)phenethyl)cyclohexanol was preparedfollowing the method shown in Scheme 17.

Step 1: Diethylazodicarboxylate (17.4 g, 100 mmol) was added slowly to asolution of 3-iodophenol (18.5 g, 84 mmol), alcohol 80 14.73 g, 84mmol), and triphenyl phosphine (26.2 g, 100 mmol) in THF (200 mL) at 0°C. under argon. The reaction was allowed to warm and stirred at roomtemperature for 2 hours, heated to 80° C. for 6 hours, then concentratedunder reduced pressure. The residue was triturated with diethyl etherand the resulting white solids removed by filtration. The filtrate wasconcentrated under reduce pressure and the residue partitioned in ethylacetate and 1 N NaOH. The organics were combined, washed with brine, andconcentrated under reduced pressure. The residue was purified by flashchromatography (5-20% ethyl acetate/hexanes gradient) on silica gel,giving the carbamate 81 as an impure yellow oil which was carried on tothe next step without further purification. Yield (17.3 g, 54%).

Step 2: HCl (12 mL of a 4.8 M solution in iPrOH, 56 mmol) was added to asolution of carbamate 81 (10 g, 28 mmol) in ethyl acetate (25 mL). Afterstirring 1 h, the reaction mixture was filtered and the solids driedunder reduced pressure, giving the hydrochloride salt 82 as a whitesolid which was carried on to the next step without purification oranalysis. Yield (2.9 g, 30%).

Step 3: Protection of amine hydrochloride 82 with ethyltrifluoroacetateaccording the method used in Example 9, except that 1 equivalent of TEAwas used and the reaction was carried out in dichloromethane, gavetrifluoroamide 83 as a yellow oil. Yield (3.4 g, quantitative). ¹H NMR(400 MHz, CDCl₃) δ 7.29-7.33 (m, 1H), 7.24-7.26 (m, 1H), 6.99 (t, J=8.0Hz, 1H), 6.83-6.87 (m, 1H), 6.75 (brs, 1H), 4.45-4.55 (m, 1H), 3.52-3.53(m, 1H), 3.40-3.50 (m, 1H), 1.29 (d, J=6.4 Hz, 3H).

Step 4: A mixture of trifluoroamide 83 (500 mg, 1.34 mmol),1-ethynylcyclohexanol (250 mg, 2.01 mmol), copper iodide (25 mg, 0.13mmol), tri-o-tolylphosphine (40 mg, 0.13 mmol), TEA (0.279 mL, 2.01 mL),and bis-chloro-triphenylphosphine palladium (91 mg, 0.13 mmol) in DMF(13 mL) was degassed, placed under argon atmosphere, and stirredovernight at 90° C. The reaction mixture was filtered and the filtratepartitioned in EtOAc/water. The organic layers were combined and washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography(10-30% EtOAc/hexanes gradient) giving alkyne 84 as a yellow glassy oil.Yield (0.322 g, 65%).). ¹H NMR (400 MHz, CDCl₃) δ 7.21 (t, J=8.0 Hz,1H), 7.04-7.08 (m, 1H), 6.94-6.96 (m, 1H), 6.83-6.87 (m, 1H), 6.81 (brs,1H), 4.48-4.57 (m, 1H), 3.72-3.80 (m, 1H), 3.39-3.49 (m, 1H), 1.85-2.04(m, 3H), 1.50-1.80 (m, 8H), 1.29 (d, J=6.4 Hz, 3H).

Step 5: Deprotection of alkyne 84 according to the method used inExample 2 gave amine 851 as a yellow oil. Yield (0.200 g, 85%). ¹H NMR(400 MHz, CDCl₃) δ 7.18 (t, J=8.0 Hz, 1H), 6.96-7.02 (m, 2H), 6.84-6.88(m, 1H), 4.30-4.38 (m, 1H), 2.87 (d, J=5.2 Hz, 2H), 1.85-2.02 (m, 2H),1.50-1.80 (m, 11H), 1.25 (d, J=6.4 Hz, 3H). ESI MS m/z 274.3 [m+H]⁺.

Step 6: Hydrogenation of amine 85 according to the method used inExample 2 followed by flash chromatography (2% (7N NH₃/CH₃OH)/CH₂Cl₂)gave Example 83 as a colorless oil. Yield (0.045 g, 51%). ¹H NMR (400MHz, CDCl₃) δ 7.10 (t, J=8.0 Hz, 1H), 6.64-7.73 (m, 3H), 4.27 (dddd,J=6.0 Hz, 1H), 2.81 (d, J=2.8 Hz, 2H), 2.59 (m, 2H), 1.67 (m, 2H),1.30-1.60 (m, 12H), 1.15-1.30 (m, 4H). ESI MS m/z 278.4 [m+H]+, 260.3[m+H−OH]⁺.

Example 84 Preparation of1-(3-(2-aminoethoxy)phenyl)-4-methylpentan-3-ol

1-(3-(2-Aminoethoxy)phenyl)-4-methylpentan-3-ol was prepared followingthe method used in Example 9.

Step 1: Sonogashira reaction of bromide 19 with 4-methyl-pent-1-yn-3-olgave2,2,2-trifluoro-N-(2-(3-(3-hydroxy-4-methylpent-1-ynyl)phenoxy)ethyl)acetamideas yellow oil. Yield (0.51 g, 21%): ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.27(m, 1H), 7.08-7.12 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 6.88 (dd, 1H, J=6.8Hz, 1.6, 1H), 6.71 (bs, 1H), 4.32 (s, 2H), 4.09 (t, J=5.2 Hz, 2H),3.77-3.82 (m, 2H), 1.77-1.83 (m, 1H), 0.94-0.99 (m, 6H).

Step 2: Deprotection of2,2,2-trifluoro-N-(2-(3-(3-hydroxy-4-methylpent-1-ynyl)phenoxy)ethyl)acetamidegave 1-(3-(2-Aminoethoxy)phenyl)-4-methylpent-1-yn-3-ol as yellow oil.Yield (0.160 g, 47%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22-7.30 (m, 1H),6.90-7.00 (m, 3H), 4.21 (d, J=5.6 Hz, 1H), 3.93 (t, J=5.2 Hz, 2H), 2.87(bs, 2H), 1.77-1.83 (m, 1H), 0.94-0.99 (m, 6H). ¹³C NMR (100 MHz,DMSO-d₆) δ 158.5, 129.8, 123.7, 116.7, 115.2, 91.0, 83.6, 69.9, 66.3,40.7, 34.3, 18.3, 17.7. ESI MS m/z 234 [M+1]⁺.

Step 2: A solution of 1-(3-(2-Aminoethoxy)phenyl)-4-methylpent-1-yn-3-ol(0.56 g, 2.4 mmol) in EtOH (30 mL) was degassed and purged withnitrogen. To this was added Pd on C (0.05 g, 10%). The flask wasevacuated and purged with hydrogen thrice. This suspension was thenstirred at room temperature under hydrogen balloon for overnight. Thereaction mixture was filtered through a pad of Celite and the filtercake was washed with ethanol.

The filtrate was concentrated to afford Example 1. Yield (0.38, 66%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.14-7.18 (m, 1H), 6.71-6.76 (m, 3H), 3.91 (t,J=5.6 Hz, 2H), 3.12-3.17 (m, 1H), 2.89 (t, J=5.6 Hz, 2H), 2.65-2.73 (m,1H), 2.46-2.50 (m, 1H), 1.46-1.64 (m, 3H), 0.8 (t, J=5.6 Hz, 2H). ¹³CNMR (100 MHz, DMSO-d₆) δ 159.0, 144.8, 129.7, 121.1, 115.0, 112.0, 74.2,69.6, 41.1, 36.2, 33.7, 32.4, 19.4, 18.0. MS: 238 [M+1]+.

Example 85 Preparation of 3-amino-1-(3-phenethylphenyl)propan-1-ol

3-Amino-1-(3-phenethylphenyl)propan-1-ol was prepared following themethod used in Example 79.

Step 1: Sonogashira reaction of 39 with ethynylbenzene gave tert-butyl3-hydroxy-3-(3-(phenylethynyl)phenyl)propylcarbamate as brown oil. Yield(0.911 g, 85%): ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.55 (m, 3H), 7.42-7.44(m, 1H), 7.30-7.37 (m, 5H), 4.87 (bs, 1H), 4.74-4.76 (m, 1H), 3.46-3.51(m, 1H), 3.41 (bs, 1H), 3.13-3.19 (m, 1H), 1.79-1.88 (m, 2H), 1.44 (s,9H).

Step 2: Reduction of tert-butyl 3-hydroxy-3-(3-(phenylethynyl)phenyl)propylcarbamate gave tert-butyl 3-hydroxy-3-(3-phenethylphenyl) propylcarbamate as yellow oil. Yield (0.824 g, 91%): ¹H NMR (400 MHz, CDCl₃) δ7.24-7.29 (m, 3H), 7.16-7.21 (m, 5H), 7.10 (d, J=7.2 Hz, 1H), 4.86 (bs,1H), 4.69-4.73 (m, 1H), 3.46-3.49 (m, 1H), 3.13-3.19 (m, 1H), 3.10 (bs,1H), 2.91 (s, 4H), 1.80-1.88 (m, 2H), 1.46 (s, 9H).

Step 3: Deprotection of tert-butyl 3-hydroxy-3-(3-phenethyl phenyl)propyl carbamate gave Example 85 as off-white semi-solid. Yield (0.391g, 59%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.11-7.29 (m, 9H), 4.64 (t, J=7.2Hz, 1H), 2.79-2.86 (m, 6H), 1.79-1.84 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 145.7, 142.0, 141.8, 128.8, 128.7, 128.5, 127.5, 126.3,126.0, 123.6, 70.2, 37.7, 37.6, 37.1, 36.8. MS: 256 [M+1]⁺.

Example 86 Preparation of5-(3-(3-amino-1-hydroxypropyl)phenyl)-N,N-dimethylpentanamide

5-(3-(3-Amino-1-hydroxypropyl)phenyl)-N,N-dimethylpentanamide wasprepared following the method used in Example 19.

Step 1: Sonogashira reaction of 43 with pent-4-ynoic acid dimethylamideyielded5-(3-(1-hydroxy-3-(2,2,2-trifluoroacetamido)propyl)phenyl)-N,N-dimethylpent-4-ynamideas dark yellow oil. Yield (0.33 g, 48%). This compound had some tracesof the starting material and was used without further purification.

Step 2: Reduction reaction of 5-(3-(1-hydroxy-3-(2,2,2-trifluoroacetamido) propyl)phenyl)-N,N-dimethylpent-4-ynamide in EtOH gave5-(3-(1-hydroxy-3-(2,2,2-trifluoroacetamido)propyl)phenyl)-N,N-dimethylpentanamideas yellow oil. Yield (0.63 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ 7.62 (bs,1H), 7.24-7.28 (m, 1H), 7.19 (s, 1H), 7.12 (m, 2H), 4.85 (t, J=6.8 Hz,1H), 3.57-3.65 (m, 1H), 3.35-3.44 (m, 1H), 2.99 (s, 3H), 2.92 (s, 3H),2.65 (t, J=6.8 Hz, 2H), 2.29 (t, J=6.8 Hz, 2H), 1.98-2.03 (m, 2H),1.62-1.68 (m, 4H).

Step 3: Deprotection reaction of 5-(3-(1-hydroxy-3-(2,2,2-trifluoroacetamido)propyl)phenyl)-N,N-dimethylpentanamide in MeOH—H₂O system atRT for 16 h, gave a yellow oil which upon purification by flashchromatography (0-10% MeOH—NH₃ (9.5:0.5)-DCM gradient) yielded Example86 as pale yellow oil. Yield (0.24 g, 54%): ¹H NMR (400 MHz, DMSO-d₆) δ7.19 (t, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.04 (d,J=7.6 Hz, 1H), 4.55-4.59 (m, 1H), 2.91 (s, 3H), 2.76 (s, 3H), 2.52-2.59(m, 4H), 2.26 (t, J=7.6 Hz, 2H), 1.61-1.71 (m, 2H), 1.44-1.56 (m, 4H).¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 146.4, 141.7, 127.8, 126.4, 125.5,123.0, 71.3, 42.1, 36.7, 35.1, 34.7, 32.2, 30.6, 24.3. MS: 279 [M+1]⁺.

Example 87 Preparation of 5-(3-(3-aminopropyl)phenyl)pentan-1-ol

5-(3-(3-Aminopropyl)phenyl)pentan-1-ol was prepared following the methodused in Example 76.

Step 1: Sonogashira reaction of bromide 57 with 4-pentyn-1-ol gavetert-butyl 3-(3-(5-hydroxypent-1-ynyl)phenyl)propylcarbamate as yellowoil. Yield (0.653 g, 59%): ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.23 (m, 3H),7.08 (d, J=7.2 Hz, 1H), 4.53 (bs, 1H), 3.83 (t, J=6.0 Hz, 2H), 3.10-3.18(m, 2H), 2.60 (t, J=7.8 Hz, 2H), 2.54 (t, J=7.0 Hz, 2H), 1.83-1.90 (m,2H), 1.74-1.82 (m, 2H), 1.44 (s, 9H).

Step 2: Reduction of tert-butyl 3-(3-(5-hydroxypent-1-ynyl)phenyl)propylcarbamate gave tert-butyl 3-(3-(5-hydroxypentyl)phenyl)propylcarbamateas yellow oil. Yield (0.628 g, 95%): ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.21(m, 1H), 6.97-7.02 (m, 3H), 4.54 (bs, 1H), 3.71 (t, J=7.0 Hz, 2H),3.12-3.17 (m, 2H), 2.58-2.64 (m, 4H), 1.77-1.84 (m, 2H), 1.56-1.67 (m,4H), 1.44 (s, 9H), 1.37-1.42 (m, 2H).

Step 3: BOC-deprotection of tert-butyl 3-(3-(5-hydroxypentyl)phenyl)propylcarbamate gave Example 8 as brown oil. Yield (0.19 g, 43%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.12-7.17 (m, 1H), 6.94-6.98 (m, 3H), 3.37 (t,J=6.4 Hz, 2H), 2.49-2.57 (m, 6H), 1.58-1.65 (m, 2H), 1.50-1.57 (m, 2H),1.40-1.47 (m, 2H), 1.27-1.33 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆): 142.6,142.5, 128.8, 128.5, 126.0, 61.1, 41.4, 35.7, 35.2, 33.0, 32.8, 31.4,25.7. MS: 222 [M+1]

Example 88 Preparation of 2-(3-(4-methoxybutyl)phenoxy)ethanamine

2-(3-(4-Methoxybutyl)phenoxy)ethanamine was prepared following themethod used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with 4-methoxybut-1-yne gave2,2,2-trifluoro-N-(2-(3-(4-methoxybut-1-ynyl)phenoxy)ethyl)acetamide asyellow oil. Yield (0.45 g, 45%): This material was directly utilized forthe deprotection reaction.

Step 2: The reduction of 2,2,2-trifluoro-N-(2-(3-(4-methoxybut-1-ynyl)phenoxy)ethyl)acetamide afforded2,2,2-trifluoro-N-(2-(3-(4-methoxybutyl)phenoxy) ethyl)acetamide asyellow oil. Yield (0.34 g, 75%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15-7.20(m, 1H), 6.71-6.78 (m, 3H), 4.06 (t, J=5.6 Hz, 2H), 3.53-3.58 (m, 2H),3.31 (t, J=6.8 Hz, 2H), 3.20 (s, 3H), 2.54 (t, J=7.6 Hz, 2H), 1.54-1.62(m, 2H), 1.44-1.52 (m, 2H). MS: 318 [M−1].

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-(4-methoxybutyl)phenoxy)ethyl)acetamide gave Example 88 as yellow oil. Yield (0.18 g,76%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15-7.20 (m, 1H), 6.71-6.78 (m, 3H),3.93 (t, J=5.6 Hz, 2H), 3.31 (t, J=6.2 Hz, 2H), 3.20 (s, 3H), 2.93 (t,J=5.6 Hz, 2H), 2.54 (t, J=7.4 Hz, 2H), 1.52-1.60 (m, 2H), 1.43-1.50 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.0, 144.2, 129.7, 121.1, 115.0,112.1, 72.1, 69.1, 58.3, 40.9, 35.4, 29.1, 27.9. MS: 224 [M+1]+

Example 89 Preparation of 1-(3-(2-aminoethoxy)phenethyl)cyclooctanol

1-(3-(2-Aminoethoxy)phenethyl)cyclooctanol was prepared following themethod used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with 1-ethynylcyclooctanolgave2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclooctyl)ethynyl)phenoxy)ethyl)acetamideas a clear oil. Yield (1.3 g, 72%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (d,J=8.0 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.91-6.96 (m, 2H), 4.09-4.13 (m,2H), 2.00-2.06 (m, 6H), 1.48-1.72 (m, 11H).

Step 2: The reduction of 2,2,2-trifluoro-N-(2-(3-((1-hydroxycyclooctyl)ethynyl)phenoxy)ethyl)acetamide afforded2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclooctyl)ethyl)phenoxy)ethyl)acetamideas yellow oil. Yield (0.36 g, 78%): ¹H NMR (400 MHz, DMSO-d₆) δ7.14-7.18 (m, 1H), 6.72-6.78 (m, 3H), 4.06 (t, J=6.0 Hz, 2H), 3.42-3.45(m, 2H), 2.55-2.59 (m, 2H), 1.30-1.71 (m, 16H). MS: 386 [M−1].

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclooctyl)ethyl)phenoxy)ethyl)acetamide gave Example 89 as yellow oil. Yield(0.097 g, 37%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.18 (m, 1H), 6.70-6.76(m, 3H), 3.93 (t, J=5.6 Hz, 2H), 2.92 (t, J=5.6 Hz, 2H), 2.54-2.59 (m,2H), 1.31-1.70 (m, 16H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.5, 144.9,129.2, 120.6, 114.5, 111.4, 72.6, 68.6, 43.5, 40.4, 35.6, 29.3, 27.9,24.6, 22.0. MS: 292 [M+1]⁺.

Example 90 Preparation of3-amino-1-(3-(4-methylpentyl)phenyl)propan-1-ol

3-Amino-1-(3-(4-methylpentyl)phenyl)propan-1-ol was prepared followingthe method used in Example 63.

Step 1: Sonogashira reaction of 43 with 4-methyl-pent-1-yne yielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-methylpent-1-ynyl)phenyl)propyl)acetamideas dark brown oil. Yield (0.94 g, 94%): ¹H NMR (400 MHz, CDCl₃) δ 7.38(s, 1H), 7.25-7.35 (m, 3H), 4.86 (m, 1H), 3.67-3.72 (m, 1H), 3.38-3.44(m, 1H), 2.30 (d, J=6.4 Hz, 2H), 2.28 (bs, 1H), 1.87-1.99 (m, 3H), 1.05(d, J=6.8 Hz, 6H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-methylpent-1-ynyl)phenyl)propyl)acetamidegave 3-(3-(3-amino-1-hydroxypropyl)phenyl)prop-2-yn-1-ol as yellow oil.Yield (0.508 g, 76%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.33 (s, 1H),7.23-7.29 (m, 3H), 5.12 (bs, 2H), 4.66 (t, J=6.4 Hz, 1H), 2.68 (t, J=6.8Hz, 2H), 2.32 (d, J=6.4 Hz, 2H), 1.82-1.86 (m, 1H), 1.67-1.72 (m, 2H),0.95 (d, J=6.8 Hz, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ 146.8, 130.0,128.9, 128.8, 125.7, 123.4, 89.6, 82.1, 70.7, 40.6, 38.3, 28.1, 28.0,22.3. ESI MS m/z 232 [M+1]⁺.

Step 3: A mixture of3-amino-1-(3-(4-methylpent-1-ynyl)phenyl)propan-1-ol (0.3 g, 1.3 mmol)and HCl in Dioxane (1 mL, 4M) in 2-PrOH was stirred at RT for 30 min.The solvent was removed under reduced pressure and the hydrochloridesalt thus obtained was dissolved in EtOH (10 mL). After purging theflask with nitrogen, Pd on C (0.040 g, 10%) was added. The flask wasevacuated and re-filled with hydrogen after which it was stirred underH₂ balloon for about 14 h. The reaction mixture was filtered through apad of Celite and the filtrate was evaporated to dryness under reducedpressure. The product obtained was purified by flash chromatography(0-10% MeOH-DCM gradient) to yield Example 90 hydrochloride as whitesolid. Yield (0.231 g, 65%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.23 (t, J=7.2Hz, 1H), 7.12 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H),4.62 (t, J=7.6 Hz, 1H), 2.77-2.89 (m, 2H), 2.50-2.54 (m, 2H), 1.78-1.84(m, 2H), 1.48-1.57 (m, 3H), 1.13 (m, 2H), 0.83 (d, J=6.8 Hz, 6H). ¹³CNMR (100 MHz, DMSO-d₆) δ 145.7, 142.6, 128.5, 127.3, 125.9, 123.4, 70.2,38.5, 37.1, 36.8, 36.0, 29.4, 27.7, 23.0. MS: 236 [M+1]⁺.

Example 91 Preparation of5-(3-(3-amino-1-hydroxypropyl)phenyl)pentan-1-ol

5-(3-(3-Amino-1-hydroxypropyl)phenyl)pentan-1-ol was prepared followingthe method used in Example 63.

Step 1: Sonogashira reaction of 43 with pent-4-yn-1-ol gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(5-hydroxypent-1-ynyl)phenyl)propyl)acetamideas brown oil. Yield (1.46 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ 7.38 (s,1H), 7.22-7.34 (m, 3H), 4.86 (d, J=8.0 Hz, 1H), 3.83 (t, J=5.2 Hz, 2H),3.65-3.69 (m, 1H), 3.38-3.42 (m, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.38 (bs,1H) 1.93-1.99 (m, 2H), 1.83-1.88 (m, 2H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(5-hydroxypent-1-ynyl)phenyl)propyl)acetamidegave 5-(3-(3-amino-1-hydroxypropyl)phenyl)pent-4-yn-1-ol as yellow oil.Yield (0.64 g, 65%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.32 (s, 1H), 7.25-7.28(m, 2H), 7.20-7.22 (m, 1H) 4.66 (t, J=6.4 Hz, 1H), 4.55 (bs, 1H), 3.52(t, J=6.4 Hz, 2H), 2.57-2.66 (m, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.60-1.70(m, 4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 147.2, 129.8, 129.0, 128.7, 125.7,123.3, 90.6, 81.1, 71.1, 59.9, 41.8, 38.9, 32.0, 15.7; ESI MS m/z 234[M+1]⁺.

Step 3: A solution of 5-(3-(3-amino-1-hydroxypropyl)phenyl)pent-4-yn-1-ol in IPA (20 mL) was degassed and purged with nitrogen. Tothis was added Pd on C (0.2 g, 10%). The flask was evacuated and filledwith hydrogen. After repeating this procedure thrice, the reactionmixture was stirred under H₂ balloon for about 14 h following which itwas filtered through Celite and concentrated under reduced pressure.Upon purification by flash chromatography (0-10% MeOH—NH₃ (9.5:0.5)-DCMgradient) Example 91 was obtained as yellow oil. Yield (0.208 g, 85%):¹H NMR (400 MHz, DMSO-d₆) δ 7.23 (t, J=7.6 Hz, 1H), 7.10-7.13 (m, 2H),7.05 (d, J=7.6 Hz, 1H), 4.63 (t, J=6.4 Hz, 1H), 3.36 (t, J=6.8 Hz, 2H),2.72 (t, J=6.8 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 1.73 (m, 2H), 1.59 (m,2H), 1.45 (m, 2H), 1.39 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 145.8,142.0, 127.9, 126.7, 125.5, 122.9, 70.6, 60.6, 37.7, 35.3, 32.3, 31.0,25.2. MS: 238 [M+1]⁺.

Example 92 Preparation of 3-(3-(4-methylpentyl)phenyl-propan-1-amine

3-(3-(4-Methylpentyl)phenyl-propan-1-amine was prepared following themethod used in Example 76.

Step 1: Sonogashira coupling of bromide 57 (0.5 g, 1.5 mmol) with4-methyl-1-pentyne (0.2 mL, 2.4 mmol) gave tert-butyl3-(4-methylpent-1-ynyl)phenylcarbamate. Yield (0.35 g, 69%). ¹H NMR (400MHz, CDCl₃) δ 7.16-7.28 (m, 3H), 7.07 (d, J=7.2 Hz, 1H), 4.50 (bs, 1H),3.12-3.15 (m, 2H), 2.60 (d, J=7.6 Hz, 2H), 2.29 (d, J=6.8 Hz, 2H),1.84-1.94 (m, 2H), 1.74-1.82 (m, 1H), 1.44 (s, 9H), 1.04 (d, J=6.8 Hz,6H).

Step 2: Reduction of tert-butyl 3-(3-(4-methylpent-1-ynyl)phenyl)propylcarbamate gave tert-butyl 3-(3-(4-methylpentyl)phenyl)propylcarbamate asyellow oil. Yield (0.309 g, 88%): ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.21(m, 1H), 6.98-7.02 (m, 3H), 3.12-3.18 (m, 2H), 2.61 (t, J=7.8 Hz, 2H),2.55 (t, J=7.8 Hz, 2H), 1.74-1.83 (m, 2H), 1.51-1.62 (m, 2H), 1.44 (s,9H), 1.18-1.26 (m, 3H), 0.87 (d, J=6.8 Hz, 6H).

Step 3: BOC-deprotection of tert-butyl 3-(3-(4-methylpentyl)phenyl)propylcarbamate gave Example 92 hydrochloride as an off-white solid.Yield (0.1 g, 53%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.18-7.22 (m, 1H),7.0-7.03 (m, 3H), 2.76 (t, J=7.6 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 2.52(t, J=7.6 Hz, 2H), 1.79-1.87 (m, 2H), 1.50-1.59 (m, 3H), 1.14-1.20 (m,2H), 0.85 (d, J=6.8 Hz, 6H). ¹³C NMR (100 MHz, DMSO-d₆): 142.4, 140.7,128.3, 128.2, 125.9, 125.5, 38.3, 38.1, 35.4, 31.8, 28.8, 28.7, 27.2,22.5. MS: 220 [M+1]

Example 93 Preparation of5-(3-(2-aminoethoxy)phenyl)-N-methylpentanamide

5-(3-(2-Aminoethoxy)phenyl)-N-methylpentanamide was prepared followingthe method used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with pent-4-ynoic acidN-methyl amide gaveN-methyl-5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pent-4-ynamideas a brown oil. Yield (0.45 g, 58%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.02(bs, 1H), 7.18-7.24 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 6.83(dd, J=8.0, 2.4 Hz, 1H), 6.76 (bs, 1H), 4.09 (t, J=5.2 Hz, 2H),3.76-3.81 (m, 2H), 2.85 (d, J=4.8 Hz, 3H), 2.76 (t, J=7.4 Hz, 2H), 2.47(t, J=7.4 Hz, 2H).

Step 2: The reduction of N-methyl-5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pent-4-ynamide affordedN-methyl-5-(3-(2-(2,2,2-trifluoroacetamido) ethoxy)phenyl)pentanamide asyellow oil. Yield (0.22 g, 47%): MS: 345 [M−1]. This product wasutilized as such for the next transformation.

Step 3: Deprotection ofN-methyl-5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pentanamidegave 5-(3-(2-aminoethoxy)phenyl)-N-methylpentanamide. Treatment of5-(3-(2-aminoethoxy)phenyl)-N-methylpentanamide with HCl in dioxane (4M) gave Example 93 hydrochloride as a white solid. Yield (0.08 g, 44%):¹H NMR (400 MHz, DMSO-d₆) δ 7.18-7.23 (m, 1H), 6.77-6.81 (m, 3H), 4.12(t, J=4.8 Hz, 2H), 3.19 (t, J=4.8 Hz, 2H), 2.50-2.53 (m, 5H), 2.05 (t,J=6.8 Hz, 2H), 1.43-1.52 (m, 4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 172.4,157.8, 143.8, 129.3, 121.2, 114.7, 111.8, 64.0, 38.2, 35.1, 34.8, 30.5,25.4, 24.9. MS: 251 [M+1]⁺.

Example 94 Preparation of5-(3-(2-aminoethoxy)phenyl)-N,N-dimethylpentanamide

5-(3-(2-Aminoethoxy)phenyl)-N,N-dimethylpentanamide was preparedfollowing the method used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with pent-4-ynoic acidN,N-dimethyl amide gaveN,N-dimethyl-5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pent-4-ynamideas a brown oil. Yield (0.9 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ7.18-7.23 (m, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.92 (s, 1H), 6.83 (dd,J=8.4, 2.4 Hz, 1H), 4.09 (t, J=5.0 Hz, 2H), 3.76-3.80 (m, 2H), 2.98 (s,3H), 2.96 (s, 3H), 2.76 (t, J=7.6 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H).

Step 2: The reduction ofN,N-dimethyl-5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pent-4-ynamideafforded N,N-dimethyl-5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pentanamide as yellow oil. Yield (0.4 g, 88%): MS: 361[M+1]⁺. This product was pure enough to be utilized as such for the nexttransformation.

Step 3: Deprotection of N,N-dimethyl-5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pentanamide gave Example 94 as yellow oil. Yield (0.18 g,61%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.16-7.21 (m, 1H), 6.74-6.79 (m, 3H),4.0 (t, J=5.4 Hz, 2H), 3.02 (t, J=5.4 Hz, 2H), 2.93 (s, 3H), 2.79 (s,3H), 2.54 (t, J=7.2 Hz, 2H), 2.28 (t, J=7.4 Hz, 2H), 1.51-1.60 (m, 2H),1.44-1.50 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 172.3, 158.7, 144.3,129.7, 121.4, 115.1, 112.1, 67.6, 37.2, 35.4, 35.2, 32.6, 30.9, 24.7.MS: 265 [M+1]

Example 95 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenethyl)cyclooctanol

1-(3-(3-Amino-1-hydroxypropyl)phenethyl)cyclooctanol was preparedfollowing the method used in Example 19.

Step 1: Sonogashira reaction of 43 with 3-methylhex-1-yn-3-ol gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhex-1-ynyl)phenyl)propyl)acetamideas brown oil. Yield (0.908 g, 90%): ¹H NMR (400 MHz, CDCl₃) δ 7.37 (s,1H), 7.30-7.35 (m, 1H), 7.26-7.28 (m, 2H), 4.83-4.86 (m, 1H), 3.66-3.69(m, 1H), 3.39-3.42 (m, 1H), 2.60 (bs, 1H), 2.11 (bs, 1H), 1.94-1.99 (m,2H), 1.69-1.74 (m, 2H), 1.65 (s, 3H), 1.54-1.57 (m, 2H), 0.97 (t, J=7.2Hz, 3H).

Step 2: Reduction of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhex-1-ynyl)phenyl)propyl)acetamideyielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhexyl)phenyl)propyl)acetamideas yellow oil. Yield (0.99 g, 90%). This compound was utilized as suchfor the next transformation.

Step 3: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhexyl)phenyl)propyl)acetamidegave a yellow oil, which upon purification by flash chromatography(0-10% MeOH—NH₃ (9.5:0.5)-DCM gradient) yielded Example 95 as a clearoil. Yield (0.597 g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (t, J=7.2Hz, 1H), 7.12 (s, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H),4.60 (t, J=6.4 Hz, 1H), 2.70-2.73 (m, 2H), 2.55-2.58 (m, 2H), 1.69-1.74(dd, J=6.4 Hz, 12.8 Hz, 2H), 1.55-1.58 (m, 2H), 1.17-1.37 (m, 4H), 1.07(s, 3H), 0.86 (t, J=7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 146.0,142.8, 128.0, 126.7, 125.4, 122.8, 70.6, 70.5, 44.1, 43.9, 37.7, 30.0,26.8, 16.8, 14.8. MS: 266 [M+1].

Example 96 Preparation of 5-(3-(2-aminoethoxy)phenyl)pentanamide

5-(3-(2-Aminoethoxy)phenyl)pentanamide was prepared following the methodused in Example 64.

Step 1: Sonogashira reaction of bromide 19 with pent-4-ynoic acid amidegave 5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pent-4-ynamide as aclear oil. Yield (0.8 g, 50%): This compound was used without furtherpurification in the next step.

Step 2: The reduction of5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pent-4-ynamide afforded5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl) pentanamide as yellowoil. Yield (0.6 g, 54%): MS: 331 [M−1].

Step 3: Deprotection of5-(3-(2-(2,2,2-trifluoroacetamido)ethoxy)phenyl)pentanamide gave Example96 as yellow oil. Yield (0.2 g, 47%): ¹H NMR (400 MHz, DMSO-d₆) δ7.15-7.20 (m, 1H), 6.73-6.77 (m, 3H), 3.96 (t, J=5.6 Hz, 2H), 2.94 (t,J=5.6 Hz, 2H), 2.53 (t, J=7.2 Hz, 2H), 2.05 (t, J=7.2 Hz, 2H), 1.44-1.54(m, 4H). ¹³C NMR (100 MHz, DMSO-d₆) δ 174.7, 158.5, 144.3, 129.7, 121.6,115.1, 112.2, 65.5, 39.2, 35.4, 31.0, 25.2. MS: 237 [M+1]⁺.

Example 97 Preparation of5-(3-(3-aminopropyl)phenyl)-N,N-dimethylpentanamide

5-(3-(3-Aminopropyl)phenyl)-N,N-dimethylpentanamide was preparedfollowing the method used in Example 19.

Step 1: Sonogashira reaction of 43 with N-methylpent-4-ynamide gave5-(3-(1-hydroxy-3-(2,2,2-trifluoroacetamido)propyl)phenyl)-N-methylpent-4-ynamideas brown oil. Yield (0.661 g, 60%): ¹H NMR (400 MHz, CDCl₃) δ 8.0 (bs,1H), 7.43-7.48 (m, 1H), 7.37 (s, 1H), 7.30 (d, J=6.8 Hz, 2H), 5.66 (bs,1H), 4.83-4.85 (m, 1H), 3.63-3.69 (m, 1H), 3.37-3.44 (m, 1H), 2.84 (d,J=4.8 Hz, 3H), 2.72 (t, J=7.6 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H), 1.92-2.02(m, 2H).

Step 2: Reduction of 5-(3-(1-hydroxy-3-(2,2,2-trifluoro acetamido)propyl)phenyl)-N-methylpent-4-ynamide using EtOH as the solvent yielded5-(3-(1-hydroxy-3-(2,2,2-trifluoro acetamido)propyl)phenyl)-N-methylpentanamide as yellow oil. Yield (0.911 mg, 83%). ¹H NMR (400 MHz,CDCl₃) δ 8.0 (bs, 1H), 7.27 (t, J=7.2 Hz, 1H), 7.16 (s, 1H), 7.14 (d,J=7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 5.56 (bs, 1H), 4.83-4.86 (m, 1H),3.54-3.60 (m, 1H), 3.37-3.44 (m, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.63 (t,J=7.6 Hz, 2H), 2.12 (t, J=7.6 Hz, 2H), 1.96-2.0 (m, 2H), 1.58-1.67 (m,4H).

Step 3: Deprotection of 5-(3-(1-hydroxy-3-(2,2,2-trifluoro acetamido)propyl)phenyl)-N-methyl pentanamide in MeOH—H₂O system at RT for 16 h,gave a yellow oil which upon purification by flash chromatography (0-10%MeOH—NH₃ (9.5:0.5)-DCM gradient) yielded Example 97 as yellowsemi-solid. Yield (0.325 g, 49%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.19 (t,J=7.2 Hz, 1H), 7.13 (s, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.00 (d, J=7.2 Hz,1H), 4.57 (t, J=6.4 Hz, 1H), 2.57 (t, J=7.2 Hz, 2H), 2.53 (d, J=4.8 Hz,3H), 2.35 (m, 2H), 2.07 (m, 2H), 1.70 (m, 2H), 1.48-1.55 (m, 4H). ¹³CNMR (100 MHz, DMSO-d₆) δ 172.9, 146.9, 142.1, 128.3, 126.9, 126.2,123.6, 71.8, 42.7, 35.6, 35.5, 31.2, 25.9, 25.5. MS: 265 [M+1]⁺.

Example 98 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenethyl)cyclobutanol

1-(3-(3-Amino-1-hydroxypropyl)phenethyl)cyclobutanol was preparedfollowing the method used in Example 79.

Step 1: Sonogashira reaction of 39 with 1-ethynyl-cyclobutanol yieldedtert-butyl 3-hydroxy-3-(3-(2-(1-hydroxycyclobutyl) ethynyl)phenyl)propylcarbamate as yellow oil. Yield (1.5 g, 70%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.45 (s, 1H), 7.27-7.34 (m, 3H), 4.85 (bs, 1H), 4.71 (m, 1H),3.48-3.51 (m, 2H), 3.14-3.16 (m, 1H), 2.50-2.52 (m, 2H), 2.30-2.49 (m,3H), 1.80-1.90 (m, 4H), 1.45 (s, 9H).

Step 2: Reduction of tert-butyl 3-hydroxy-3-(3-((1-hydroxycyclobutyl)ethynyl)phenyl)propylcarbamate in EtOH for 72 h gave tert-butyl3-hydroxy-3-(3-(2-(1-hydroxycyclobutyl)ethyl)phenyl)propylcarbamate asyellow oil. Yield (0.694 g, 92%): ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.26(m, 2H), 7.12-7.18 (m, 2H), 4.73 (bs, 1H), 4.68-4.75 (m, 1H), 3.46-3.51(m, 1H), 3.13-3.20 (m, 1H), 2.69-2.72 (m, 2H), 2.06-2.11 (m, 2H),1.96-1.99 (m, 2H), 1.56-1.93 (m. 4H), 1.45 (s, 9H).

Step 3: A mixture of tert-butyl 3-hydroxy-3-(3-(2-(1-hydroxycyclobutyl)ethyl)phenyl)propylcarbamate and HCl in Dioxane (2 mL, 4M) in ethylacetate was stirred at RT for 20 h. The mixture was concentrated todryness under reduced pressure. Purification by flash chromatography(0-10% MeOH-DCM gradient) gave Example 98 hydrochloride as pale yellowsemi-solid. Yield (0.235 g, 47%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.67-7.71(bs, 3H), 7.23 (t, J=7.6, 1H), 7.18 (s, 1H), 7.10 (d, J=7.6 Hz, 1H),7.08 (d, J=7.6 Hz, 1H), 4.93 (bs, 1H), 4.63-4.66 (m, 1H), 2.80-2.85 (m,2H), 2.50-2.59 (m, 2H), 1.93-1.97 (m, 4H), 1.81-1.85 (m, 2H), 1.71-1.76(m, 2H), 1.62-1.64 (m, 1H), 1.44-1.49 (m, 1H). ¹³C NMR (100 MHz,DMSO-d₆) δ 145.7, 143.2, 128.5, 127.4, 125.9, 123.2, 73.7, 70.2, 42.0,37.2, 36.9, 36.1, 30.1, 12.3. MS: 250 [M+1]⁺.

Example 99 Preparation of 2-(3-(2-aminoethoxy)phenethyl)cyclohexanol

2-(3-(2-Aminoethoxy)phenethyl)cyclohexanol was prepared following themethod used in Example 9.

Step 1: Sonogashira coupling of bromide 19 with 2-ethynylcyclohexanolfollowed by flash chromatography (5-50% EtOAc/hexanes gradient), gave2,2,2-trifluoro-N-(2-(3-((2-hydroxycyclohexyl)ethynyl)phenoxy)ethyl)acetamideas a yellow oil. Yield (0.88 g, 31%): ¹H NMR (400 MHz, CDCl₃) δ 7.18 (t,J=8.0 Hz, 1H), 7.01-7.04 (m, 1H), 6.90-6.98 (brs, 1H), 6.91-6.92 (m,1H), 6.79-6.83 (m, 1H), 4.05-4.07 (m, 2H), 3.74 (app q, J=5.2 Hz, 2H),3.48-3.56 (m, 1H), 2.35-2.46 (m, 2H), 2.00-2.08 (m, 1H), 1.64-1.80 (m,2H), 1.40-1.52 (m, 1H), 1.14-1.40 (m, 4H).

Step 2: Deprotection of2,2,2-trifluoro-N-(2-(3-((2-hydroxycyclohexyl)-ethynyl)phenoxy)ethyl)acetamidefollowed by purification by flash chromatography (10% (7NNH₃/MeOH)/dichloromethane) gave2-((3-(2-aminoethoxy)phenyl)ethynyl)cyclohexanol as a white solid. Yield(0.29 g, 45%): ¹H NMR (400 MHz, CDCl₃) δ 7.18 (t, J=7.6 Hz, 1H),6.98-7.03 (m, 1H), 6.93-6.95 (m, 1H), 6.83-6.86 (m, 1H), 3.96 (t, J=5.2Hz, 2H), 3.49-3.57 (m, 1H), 3.08 (brs, 2H), 2.38-2.46 (m, 1H), 2.01-2.10(m, 2H), 1.55-2.00 (brs, 1H), 1.74-1.82 (m, 2H), 1.65-1.74 (m, 2H),1.40-1.52 (m, 1H), 1.16-1.40 (m, 3H).

Step 3: Hydrogenation of2-((3-(2-aminoethoxy)phenyl)ethynyl)cyclohexanol followed by flashchromatography (10% (7N NH₃/MeOH)/dichloromethane) gave example 99 as ayellow-green oil. Yield (0.99 g, 67%): ¹H NMR (400 MHz, CDCl₃) δ 7.17 (tJ=8.0 Hz, 1H), 6.75-6.80 (m, 2H), 6.69-6.73 (m, 1H), 3.70 (t, J=5.2 Hz,2H), 3.19-3.27 (m, 1H), 3.06 (t, J=5.2 Hz, 2H), 2.66-2.79 (m, 1H),2.47-2.56 (m, 1H), 2.05-2.14 (m, 1H), 1.87-1.97 (m, 2H), 1.69-1.77 (m,1H), 1.61-1.69 (m, 1H), 1.53 (brs, 3H), 1.36-1.46 (m, 1H), 1.11-1.34 (m,4H), 0.91-1.03 (m, 1H).

Example 100 Preparation of2-(3-(3-amino-1-hydroxypropyl)phenethyl)cyclohexanol

2-(3-(3-Amino-1-hydroxypropyl)phenethyl)cyclohexanol was preparedfollowing the method used in Example 63.

Step 1: Sonogashira coupling of bromide 43 with 2-ethynylcyclohexanolfollowed by flash chromatography (5-50% EtOAc/hexanes gradient), gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamideas a yellow oil. Yield (1.9 g, 63%): ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.41(m, 1H), 7.23-7.36 (m, 4H), 4.84 (q, J=4.0 Hz, 1H), 3.62-3.72 (m, 1H),3.50-3.57 (m, 1H), 3.34-3.44 (m, 1H), 2.38-2.46 (m 1H), 2.18 (brs, 2H),1.90-2.10 (m, 4H), 1.66-1.84 (m, 2H), 1.40-1.53 (m, 1H), 1.16-1.40 (m,3H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamidefollowed by flash chromatography (10% (7N NH₃/MeOH)/dichloromethane)gave 2-((3-(3-amino-1-hydroxypropyl)phenyl)ethynyl)cyclohexanol as alight yellow glassy solid. Yield (0.402 g, 29%): ¹H NMR (400 MHz, CDCl₃)δ 7.44-7.46 (m, 1H), 7.21-7.31 (m, 3H), 4.92 (dd, J=8.8, 3.2 Hz, 1H),3.47-3.56 (m, 1H), 3.05-3.12 (m, 1H), 3.01 (brs, 4H), 2.90-2.99 (m, 1H),2.37-2.44 (m, 1H), 2.00-2.09 (m, 2H), 1.81-1.90 (m, 1H), 1.64-1.81 (m,3H), 1.40-1.52 (m, 1H), 1.14-1.40 (m, 3H).

Step 3: Hydrogenation of2-((3-(3-amino-1-hydroxypropyl)phenyl)ethynyl)cyclohexanol followed byflash chromatography (10% (7N NH₃/MeOH)/dichloromethane) gave Example100 as a yellow oil. Yield (0.153 g, 67%): ¹H NMR (400 MHz, CDCl₃) δ7.19-7.26 (m, 2H), 7.13-7.17 (m, 1H), 7.05-7.08 (m, 1H), 4.88-4.93 (dd,J⁼3.2, 8.8 Hz, 1H), 3.17-3.25 (m, 1H), 3.01-3.10 (m, 1H), 2.88-2.97 (m,1H), 2.60-2.88 (m, 5H), 2.49-2.58 (m, 1H), 2.05-2.15 (m, 1H), 1.54-1.96(m, 6H), 1.35-1.47 (m, 1H), 1.10-1.33 (m, 4H), 0.91-1.02 (m, 1H).

Example 101 Preparation of 1-(3-(2-aminoethoxy)phenethyl)cyclobutanol

1-(3-(2-Aminoethoxy)phenethyl)cyclobutanol was prepared following themethod used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with 1-ethynyl-cyclobutanolgave 2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclobutyl)ethynyl)phenoxy)ethyl)acetamide as a brown oil. Yield (0.85 g, 39%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.27-7.30 (m, 1H), 6.92-7.03 (m, 3H), 4.09-4.13 (m, 4H),3.54-3.58 (m, 2H), 2.33-2.37 (m, 2H), 2.16-2.24 (m, 2H), 1.74-1.81 (m,2H).

Step 2: A solution of 2,2,2-Trifluoro-N-(2-(3-(2-(1-hydroxycyclobutyl)ethynyl) phenoxy)ethyl)acetamide (0.45 g, 1.9 mmol) in EtOH(20 mL) was degassed and purged with nitrogen. To this was added Pd on C(0.09 g, 10%) and the flask was evacuated and filled with hydrogen. Theresulting reaction mixture was stirred at room temperature underhydrogen balloon overnight. This was followed by filteration through apad of Celite. The filter cake was washed with ethanol and the filtrateconcentrated to afford2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclobutyl)ethyl)phenoxy)ethyl)acetamide as yellow oil. Yield (0.3 g, 66%): ¹H NMR (400MHz, DMSO-d₆) δ 7.20-7.25 (m, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.78 (s, 1H),6.72 (dd, J=8.0, 2.4 Hz, 1H), 4.11 (t, J=5.0 Hz, 2H), 3.76-3.81 (m, 2H),2.67-2.72 (m, 2H), 2.01-2.14 (m, 4H), 1.92-1.96 (m, 2H), 1.22-1.26 (m,2H).

Step 3: To a stirred solution of 2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclobutyl)ethyl)phenoxy)ethyl)acetamide (0.3 g, 0.9 mmol) in MeOH-water(6: 0.5) mL was added K₂CO₃ (0.187 g, 1.4 mmol). The resulting mixturewas stirred overnight following which the solvent was removed underreduced pressure. The residue was partitioned between DCM and water andthe combined organics were washed with water followed by drying overNa₂SO₄. The filtrate was concentrated under reduced pressure to giveExample 101 as brown oil. Yield (0.12 g, 56%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.17-7.22 (m, 1H), 6.81-6.85 (m, 2H), 6.77 (dd, J=7.6, 2.0 Hz, 2H),4.12 (t, J=5.2 Hz, 2H), 3.18 (t, J=5.2 Hz, 2H), 2.52-2.60 (m, 2H),1.91-1.97 (m, 4H), 1.70-1.76 (m, 2H), 1.58-1.66 (m, 1H), 1.40-1.50 (m,1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.4, 145.1, 129.8, 121.7, 115.1,112.2, 73.7, 64.6, 41.8, 38.8, 36.1, 30.1, 12.3. MS: 236 [M+1]⁺.

Example 102 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenyl)-4-methylpentan-3-ol

1-(3-(3-Amino-1-hydroxypropyl)phenyl)-4-methylpentan-3-ol was preparedfollowing the method used in Example 79.

Step 1: Sonogashira reaction of 39 with 4-methyl-pent-1-yn-3-ol yieldedtert-butyl3-hydroxy-3-(3-(3-hydroxy-4-methylpent-1-ynyl)phenyl)propylcarbamate asdark brown oil. Yield (1.73 g, 81%): ¹H NMR (400 MHz, CDCl₃) δ 7.44 (s,1H), 7.28-7.34 (m, 3H), 4.86 (bs, 1H), 4.72 (bs, 1H), 4.39 (t, J=6.0 Hz,1H), 3.46-3.51 (m, 2H), 3.11-3.19 (m, 1H), 1.78-2.04 (m, 4H), 1.45 (s,9H), 1.02 (d, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H).

Step 2: Reduction of tert-butyl3-hydroxy-3-(3-(3-hydroxy-4-methylpent-1-ynyl)phenyl) propylcarbamateresulted in tert-butyl3-hydroxy-3-(3-(3-hydroxy-4-methylpentyl)phenyl)propylcarbamate asyellow oil. Yield (0.847 g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.28(m, 1H), 7.22 (s, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H),4.89 (bs, 1H), 4.70-4.72 (m, 1H), 3.46-3.51 (m, 1H), 3.35-3.40 (bs, 1H),3.15-3.18 (m, 2H), 2.81-2.84 (m, 1H), 2.64-2.67 (m, 1H), 1.80-1.87 (m,2H), 1.64-1.79 (m, 3H), 1.45 (s, 9H), 0.92 (d, J=6.8, 6H).

Step 3: Deprotection of tert-butyl3-hydroxy-3-(3-(3-hydroxy-4-methylpentyl)phenyl)propylcarbamate gaveExample 102 hydrochloride as pale yellow semi-solid. Yield (0.205 g,30%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (t, J=7.6 Hz, 1H), 7.13 (s, 1H),7.18 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 4.61 (t, J=6.8 Hz, 1H),3.81 (m, 1H) 3.14-3.18 (m, 1H), 2.83-2.90 (m, 2H), 2.77-2.80 (m, 1H),1.81-1.85 (m, 2H), 1.48-1.61 (m, 3H), 0.92 (d, J=6.8 Hz, 6H). ¹³C NMR(100 MHz, DMSO-d₆) δ 145.7, 143.0, 128.5, 127.4, 126.0, 125.9, 123.3,74.3, 70.2, 36.8, 36.4, 33.7, 32.5, 19.4, 18.0. MS: 252 [M+1]⁺.

Example 103 Preparation of 1-(3-(3-aminopropyl)phenethyl)cyclooctanol

1-(3-(3-Aminopropyl)phenethyl)cyclooctanol was prepared following themethod used in Example 57 except that the hydrogenation was conductedbefore the deprotection of the amine.

Step 1: Sonogashira coupling of bromide 10 with 1-ethynyl-cyclooctanolgave2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycyclooctyl)ethynyl)phenyl)propyl)acetamide.Yield (0.344 g, 47%). ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.29 (m, 2H),7.15-7.19 (m, 1H), 7.11-7.13 (m, 1H), 6.23 (bs, 1H), 3.36-3.42 (m, 2H),1.48-2.07 (m, 18H).

Step 2: Reduction of 2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclooctyl)ethynyl)phenyl)propyl) acetamide gave2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycyclooctyl)ethyl)phenyl)propyl)acetamide as yellow oil. Yield (0.895 g, 98%): ¹HNMR (400 MHz, CDCl₃) δ 7.19-7.24 (m, 1H), 7.06 (d, J=7.2 Hz, 1H), 7.02(s, 1H), 6.99 (d, J=7.2 Hz, 1H), 3.36-3.42 (m, 2H), 2.64-2.70 (m, 4H),1.89-1.96 (m, 2H), 1.32-1.87 (m, 16H).

Step 7: Deprotection of 2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycyclooctyl)ethyl)phenyl)propyl)acetamide gave Example 103 as yellow oil. Yield(0.277 g, 42%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.12-7.16 (m, 1H), 6.94-6.98(m, 3H), 2.50-2.56 (m, 6H), 1.32-1.70 (m, 18H). ¹³C NMR (100 MHz,DMSO-d₆): 143.3, 142.1, 128.2, 128.1, 125.6, 125.4, 72.6, 43.7, 40.9,35.7, 34.5, 32.5, 29.3, 28.0, 24.7, 22.0. MS: 290 [M+1]

Example 104 Preparation of5-(3-(3-amino-1-hydroxypropyl)phenyl)pentanamide

5-(3-(3-Amino-1-hydroxypropyl)phenyl)pentanamide was prepared followingthe method used in Example 19.

Step 1: Sonogashira reaction of 43 with pent-4-ynamide gave5-(3-(1-hydroxy-3-(2,2,2-trifluoroacetamido)propyl)phenyl)pent-4-ynamideas brown oil. Yield (0.6 g, 57%). This compound was utilized as such forthe next transformation. MS: 343 [M+1]⁺.

Step 2: Reduction of 5-(3-(1-hydroxy-3-(2,2,2-trifluoroacetamido)propyl)phenyl)pent-4-ynamide yielded5-(3-(1-hydroxy-3-(2,2,2-trifluoro acetamido)propyl)phenyl)pentanamideas yellow oil. Yield (0.51 g, 83%). This compound was also utilized assuch for the next transformation. MS: 347 [M+1]⁺.

Step 3: Deprotection of5-(3-(1-hydroxy-3-(2,2,2-trifluoroacetamido)propyl)phenyl)pentanamideand subsequent purification by flash chromatography (0-10% (MeOH—NH₃(9.5:0.5))-DCM gradient) gave Example 104 as clear oil. Yield (0.125 g,35%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.23 (t, J=7.6 Hz, 1H), 7.12 (s, 1H),7.10 (d, J=7.6 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 4.60 (t, J=6.4 Hz, 1H),2.77-2.89 (m, 2H), 2.56 (t, J=6.8 Hz, 2H), 2.05 (t, J=6.8 Hz, 2H),1.79-1.85 (m, 2H), 1.48-1.52 (m, 4H). ¹³C NMR (100 MHz, DMSO-d₆) δ174.7, 145.7, 142.5, 128.5, 127.4, 125.9, 123.4, 70.3, 37.1, 37.0, 35.5,35.4, 31.2, 25.2. MS: 251 [M+1]⁺.

Example 105 Preparation of3-amino-1-(3-(2-cyclooctylethyl)phenyl)propan-1-ol

3-Amino-1-(3-(2-cyclooctylethyl)phenyl)propan-1-ol was preparedfollowing the method used in Example 79.

Step 1: Sonogashira reaction of 39 with ethynyl cyclooctane yieldedtert-butyl 3-(3-(2-cyclooctylethynyl)phenyl)-3-hydroxypropylcarbamate aslight yellow oil. Yield (470 mg, 91%): ¹H NMR (400 MHz, CDCl₃) δ 7.39(s, 1H), 7.22-7.29 (m, 3H), 4.86 (bs, 1H), 4.72 (m, 1H), 3.23 (bs, 1H),3.11-3.19 (m, 1H), 2.76-2.79 (m, 2H), 1.92-1.96 (m, 2H), 1.74-1.81 (m,6H), 1.53-1.60 (m, 6H), 1.45 (s, 9H), 1.27 (m, 2H).

Step 2: Reduction of tert-butyl3-(3-(cyclooctylethynyl)phenyl)-3-hydroxypropylcarbamate gave tert-butyl3-(3-(2-cyclooctylethyl)phenyl)-3-hydroxypropylcarbamate as yellow oil.Yield (0.232 g, 89%). ¹H NMR (400 MHz, CDCl₃) δ 7.22 (t, J=7.6 Hz, 1H),7.18 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 4.89 (bs,1H), 4.72 (m, 1H), 3.49-3.54 (m, 1H), 3.13-3.21 (m, 1H), 3.07 (bs, 1H),2.58-2.62 (m, 2H), 1.82-1.87 (m, 2H), 1.63-1.68 (m, 4H), 1.49-1.57 (m,5H), 1.46-1.48 (m, 3H), 1.45 (s, 9H), 1.28-1.33 (m, 2H).

Step 3: Deprotection of tert-butyl3-hydroxy-3-(3-(2-(tetrahydro-2H-pyran-2-yl)ethyl)phenyl)propylcarbamategave a semi-solid product which was purified by flash chromatography(0-10% MeOH-DCM gradient) to obtain Example 105 hydrochloride asoff-white solid. Yield (0.194 g, 40%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.60(bs, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.14 (s, 1H), 7.11 (d, J=7.6 Hz, 1H),7.08 (d, J=7.6 Hz, 1H), 4.64 (m, 1H), 2.81-2.86 (m, 2H), 2.56-2.58 (m,2H), 1.79-1.83 (m, 2H), 1.54-1.65 (m, 7H), 1.40-1.47 (m, 9H), 1.28-1.33(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 145.7, 142.9, 128.5, 127.3, 125.9,123.3, 70.2, 37.2, 36.9, 36.8, 33.7, 32.2, 27.3, 26.3, 25.4. MS: 290[M+1]⁺.

Example 106 Preparation of3-amino-1-(3-(5-methoxypentyl)phenyl)propan-1-ol

3-Amino-1-(3-(5-methoxypentyl)phenyl)propan-1-ol was prepared followingthe method used in Example 79.

Step 1: Sonogashira reaction of 39 with 5-methoxypent-1-yne gavetert-butyl 3-hydroxy-3-(3-(5-methoxypent-1-ynyl)phenyl)propylcarbamateas brown oil. Yield (0.347 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ 7.39 (s,1H), 7.27-7.37 (m, 3H), 4.83-4.85 (bs, 1H), 4.69-4.71 (m, 1H), 3.66-3.71(m, 1H), 3.52 (t, J=6.4 Hz, 2H), 3.48 (m, 1H), 3.36 (s, 3H), 3.29 (bs,1H), 2.49 (t, J=6.4 Hz, 2H), 1.80-2.02 (m, 4H), 1.45 (s, 9H).

Step 2: Reduction of tert-butyl3-hydroxy-3-(3-(5-methoxypent-1-ynyl)phenyl)propylcarbamate yieldedtert-butyl 3-hydroxy-3-(3-(5-methoxypentyl)phenyl)propylcarbamate asyellow oil. Yield (0.299 g, 88%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.19 (t,J=7.6 Hz, 1H), 7.09 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 7.02 (d, J=7.6 Hz,1H), 4.48 (t, J=6.4 Hz, 1H), 3.27 (t, J=6.4 Hz, 2H), 3.16 (s, 3H),2.91-2.94 (m, 2H), 2.50-2.54 (m, 2H), 1.62-1.67 (m, 2H), 1.47-1.56 (m,4H), 1.33 (s, 9H), 1.23-1.28 (m, 2H).

Step 3: Deprotection of tert-butyl3-hydroxy-3-(3-(5-methoxypentyl)phenyl)propylcarbamate and subsequentpurification by flash chromatography (0-10% MeOH—NH₃ (9.5:0.5)-DCM) gaveExample 106 as clear oil. Yield (0.178 g, 72%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.20 (t, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.09 (d, J=7.6 Hz, 1H),7.04 (d, J=7.6 Hz, 1H), 4.58-4.61 (m, 1H), 3.30 (t, J=6.4 Hz, 2H), 3.18(s, 3H), 2.78-2.87 (m, 2H), 2.53-2.55 (m, 2H), 1.79-1.84 (m, 2H),1.47-1.57 (m, 4H), 1.23-1.28 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ146.4, 141.7, 127.7, 126.4, 125.6, 123.0, 71.8, 71.4, 57.7, 42.5, 38.9,35.2, 30.8, 28.8, 25.4. MS: 252 [M+1]⁺.

Example 107 Preparation of 2-(3-(5-methoxypentyl)phenoxy)ethanamine

2-(3-(5-Methoxypentyl)phenoxy)ethanamine was prepared following themethod used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with 5-methoxypent-1-yne gave2,2,2-trifluoro-N-(2-(3-(5-methoxypent-1-ynyl)phenoxy)ethyl)acetamide asa brown oil. Yield (0.305 g, 29%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22-7.27(m, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.90-6.94 (m, 2H), 4.10 (t, J=5.6 Hz,2H), 3.53-3.58 (m, 2H), 3.43 (t, J=6.4 Hz, 2H), 3.25 (s, 3H), 2.45 (t,J=7.2 Hz, 2H), 1.72-1.79 (m, 2H).

Step 2: The reduction of 2,2,2-trifluoro-N-(2-(3-(5-methoxypent-1-ynyl)phenoxy)ethyl)acetamide afforded2,2,2-trifluoro-N-(2-(3-(5-methoxypentyl)phenoxy) ethyl)acetamide asyellow oil. Yield (0.265 g, 87%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.15-7.20(m, 1H), 6.72-6.78 (m, 3H), 4.06 (t, J=5.6 Hz, 2H), 3.53-3.58 (m, 2H),3.30 (t, J=6.4 Hz, 2H), 3.19 (s, 3H), 2.53 (t, J=7.2 Hz, 2H), 1.48-1.60(m, 4H), 1.26-1.32 (m, 2H).

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-(5-methoxypentyl)phenoxy)ethyl)acetamide gave Example 107 as yellow oil. Yield (0.115 g,62%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.18 (m, 1H), 6.71-6.75 (m, 3H),3.89 (t, J=5.8 Hz, 2H), 3.28 (t, J=6.4 Hz, 2H), 3.20 (s, 3H), 2.87 (t,J=5.8 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 1.47-1.60 (m, 4H), 1.26-1.32 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.3, 144.4, 129.7, 121.7, 115.1,112.2, 72.3, 64.5, 58.2, 38.7, 35.6, 31.1, 29.3, 25.8. MS: 238 [M+1]

Example 108 Preparation of 2-(3-(2-cyclooctylethyl)phenoxy)ethanamine

2-(3-(2-Cyclooctylethyl)phenoxy)ethanamine was prepared following themethod used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with ethynylcyclooctane gaveN-(2-(3-(cyclooctylethynyl)phenoxy)ethyl)-2,2,2-trifluoroacetamide as abrown oil. Yield (0.505 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.21-7.27(m, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.88-6.92 (m, 2H), 4.09 (t, J=5.4 Hz,2H), 3.52-3.57 (m, 2H), 2.79-2.84 (m, 1H), 1.86-1.92 (m, 2H), 1.67-1.76(m, 4H), 1.47-1.58 (m, 8H).

Step 2: Reduction of 2,2,2-trifluoro-N-(2-(3-((1-hydroxycyclooctyl)ethynyl)phenoxy)ethyl)acetamide afforded2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclooctyl)ethyl)phenoxy)ethyl)acetamideas yellow oil. Yield (0.215 g, 70%): ¹H NMR (400 MHz, DMSO-d₆) δ7.14-7.19 (m, 1H), 6.74-6.78 (m, 3H), 4.05 (t, J=5.6 Hz, 2H), 3.53-3.58(m, 2H), 2.50-2.55 (m, 2H), 1.22-1.68 (m, 17H). MS: 372 [M+1]⁺.

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclooctyl)ethyl)phenoxy)ethyl)acetamide gave Example 108 as yellow oil. Yield(0.07 g, 45%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.70-6.75(m, 3H), 3.91 (t, J=5.6 Hz, 2H), 2.87 (t, J=5.6 Hz, 2H), 2.50-2.54 (m,2H), 1.22-1.66 (m, 17H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.3, 144.8,129.8, 121.7, 115.1, 112.3, 64.6, 40.6, 38.8, 36.7, 33.6, 32.2, 27.3,26.3, 25.4. MS: 276 [M+1]

Example 109 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenyl)-3-methylhexan-3-ol

1-(3-(3-Amino-1-hydroxypropyl)phenyl)-3-methylhexan-3-ol was preparedfollowing the method used in Example 19.

Step 1: Sonogashira reaction of 43 with 3-methylhex-1-yn-3-ol gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhex-1-ynyl)phenyl)propyl)acetamideas brown oil. Yield (0.908 g, 90%): ¹H NMR (400 MHz, CDCl₃) δ 7.37 (s,1H), 7.30-7.35 (m, 1H), 7.26-7.28 (m, 2H), 4.83-4.86 (m, 1H), 3.66-3.69(m, 1H), 3.39-3.42 (m, 1H), 2.60 (bs, 1H), 2.11 (bs, 1H), 1.94-1.99 (m,2H), 1.69-1.74 (m, 2H), 1.65 (s, 3H), 1.54-1.57 (m, 2H), 0.97 (t, J=7.2Hz, 3H).

Step 2: Reduction of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhex-1-ynyl)phenyl)propyl)acetamideyielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhexyl)phenyl)propyl)acetamideas yellow oil. Yield (0.99 g, 90%). This compound was utilized as suchfor the next transformation.

Step 3: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhexyl)phenyl)propyl)acetamidegave a yellow oil, which upon purification by flash chromatography(0-10% MeOH—NH₃ (9.5:0.5)-DCM gradient) yielded Example 109 as clearoil. Yield (0.597 g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (t, J=7.2Hz, 1H), 7.12 (s, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H),4.60 (t, J=6.4 Hz, 1H), 2.70-2.73 (m, 2H), 2.55-2.58 (m, 2H), 1.69-1.74(dd, J=6.4 Hz, 12.8 Hz, 2H), 1.55-1.58 (m, 2H), 1.17-1.37 (m, 4H), 1.07(s, 3H), 0.86 (t, J=7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 146.0,142.8, 128.0, 126.7, 125.4, 122.8, 70.6, 70.5, 44.1, 43.9, 37.7, 30.0,26.8, 16.8, 14.8. MS: 266 [M+1].

Example 110 Preparation of3-amino-1-(3-(2-(tetrahydro-2h-pyran-2-yl)ethyl)phenyl)propan-1-ol

3-Amino-1-(3-(2-(tetrahydro-2H-pyran-2-yl)ethyl)phenyl)propan-1-ol wasprepared following the method shown in Scheme 18 and used for Examples3, 13, 16 and 17.

Step 1: Acetonitrile addition to 3-iodobenzaldehyde (86) according tothe method used for Example 16 yielded3-hydroxy-3-(3-iodophenyl)propanenitrile (87) as yellow oil. Yield (2.58g, 55%): ¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.70 (d, J=8.0 Hz, 1H),7.38 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 5.01 (m, 1H), 2.80 (d,J=6.4, 2H), 2.40 (bs, 1H).

Step 2: Nitrile reduction of 87 according to the method used in Example17 yielded 3-amino-1-(3-iodophenyl)propan-1-ol (88) as pale yellow oil.Yield (2.63 g, quantitative yield). This compound was utilized as suchfor the next transformation. ¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H),7.58 (d, J=7.6, 1H), 7.33 (d, J=7.6, 1H), 7.06 (t, J=8.0, 1H), 4.92 (dd,J=8.8, 2.8 Hz, 1H), 3.09-3.14 (m, 1H), 2.93-2.99 (m, 1H), 1.81-1.85 (m,1H), 1.64-1.73 (m, 1H).

Step 3: BOC protection of amine 88 as in Example 17 gave tert-butyl3-hydroxy-3-(3-iodophenyl)propylcarbamate (89) as yellow oil. Yield(1.39 g, 40%). This compound was utilized as such for the nexttransformation. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.58 (d, J=7.6,1H), 7.33 (d, J=7.6, 1H), 7.07 (t, J=8.0, 1H), 4.86 (bs, 1H), 4.67 (m,1H), 3.45-3.51 (m, 2H), 3.11-3.18 (m, 1H), 1.76-1.83 (m, 2H), 1.51 (s,9H).

Step 4: Sonogashira reaction of 89 with 2-ethynyltetrahydro-2H-pyranaccording to the method in Example 3 yielded tert-butyl3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)ethynyl)phenyl)propylcarbamate (90) as dark brown oil. Yield (1.21 g, 83%): ¹H NMR (400MHz, CDCl₃) δ 7.45 (s, 1H), 7.27-7.35 (m, 3H), 4.87 (bs, 1H), 4.69-4.71(m, 1H), 4.49-4.51 (m, 1H), 4.02-4.07 (m, 1H), 3.50-3.52 (m, 1H),3.56-3.61 (m, 1H), 3.13-3.18 (m, 1H), 1.91-1.93 (m, 2H), 1.74-1.86 (m,4H), 1.51 (m, 2H), 1.43 (s, 9H).

Step 5: Reduction of tert-butyl3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)ethynyl)phenyl)propylcarbamateaccording to the method used for Example 13 gave tert-butyl3-hydroxy-3-(3-(2-(tetrahydro-2H-pyran-2-yl)ethyl)phenyl)propylcarbamate(91) as yellow oil. Yield (0.592 g, crude). ¹H NMR (400 MHz, CDCl₃) δ7.23 (t, J=7.2 Hz, 1H), 7.19 (s, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.02 (d,J=7.2 Hz, 1H), 4.89 (bs, 1H), 4.64 (t, J=7.6 Hz, 1H), 3.98-4.0 (m, 1H),3.38-3.43 (m, 2H), 3.14-3.32 (m, 3H), 2.60-2.76 (m, 2H), 1.80-1.85 (m,4H), 1.59-1.61 (m, 1H), 1.50-1.53 (m, 2H), 1.45 (s, 9H), 1.20-1.33 (m,3H).

Step 6: Deprotection of 91 according to the method used in Example 13gave a crude product which was purified by flash chromatography (0-10%MeOH-DCM gradient) to obtain Example 110 hydrochloride as an off-whitesolid. Yield (0.194 g, 40%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (t, J=7.2Hz, 1H), 7.14 (s, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H),4.64 (t, J=7.6 Hz, 1H), 3.82-3.87 (m, 2H), 3.17-3.21 (m, 2H), 2.76-2.84(m, 2H), 2.58-2.63 (m, 1H), 1.80-1.84 (m, 2H), 1.54-1.67 (m, 3H),1.43-1.51 (m, 3H), 1.16 (m, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 145.8,142.4, 128.5, 127.3, 125.9, 123.4, 76.6, 70.1, 67.9, 38.4, 37.1, 36.8,31.9, 31.7, 26.2, 23.5. MS: 264 [M+1]⁺.

Example 111 Preparation of5-(3-(3-aminopropyl)phenyl)-n-methylpentanamide

5-(3-(3-Aminopropyl)phenyl)-N-methylpentanamide was prepared followingthe method used in Example 76.

Step 1: Sonogashira coupling of bromide 57 with N-methylpent-4-ynamidegave tert-butyl 3-(3-(5-(methylamino)-5-oxopent-1-ynyl)phenyl)propylcarbamate. Yield (1.03 g, crude). ¹H NMR (400 MHz, CDCl₃) δ 7.64-7.70(m, 1H), 7.48 (d, J=6.6 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J=6.4 Hz, 1H),5.68 (bs, 1H), 4.52 (bs, 1H), 3.10-3.18 (m, 2H), 2.85 (d, J=6.8 Hz, 3H),2.75 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H),1.75-1.82 (m, 2H), 1.44 (s, 9H).

Step 2: Reduction of 5-(3-(3-Aminopropyl)phenyl)-N-methylpent-4-ynamidegave tert-butyl 3-(3-(5-(methylamino)-5-oxopentyl)phenyl)propylcarbamateas yellow oil. Yield (0.55 g, 88%): MS: 349 [M+1]

Step 3: BOC deprotection of tert-butyl3-(3-(5-(methylamino)-5-oxopentyl)phenyl)propylcarbamate gave5-(3-(3-aminopropyl)phenyl)-N-methylpentanamide hydrochloride Theproduct was isolated by adjusting the pH with conc. ammonia andextration with DCM. The organic layer was washed with water, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification by flash chromatography (0-(9.5-0.5) MeOH—NH₃)-DCMgradient) gave Example 111 as brown oil. Yield (0.107 g, 27%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.13-7.18 (m, 1H), 6.94-6.99 (m, 3H), 2.48-2.56 (m,9H), 2.05 (t, J=6.8 Hz, 2H), 1.60-1.68 (m, 2H), 1.42-1.50 (m, 4H). ¹³CNMR (100 MHz, DMSO-d₆): 172.8, 142.5, 142.4, 128.8, 128.6, 126.1, 41.2,35.6, 34.6, 32.9, 31.2, 25.8, 25.4. MS: 249 [M+1]

Example 112 Preparation of 5-(3-(3-aminopropyl)phenyl)pentanamide

5-(3-(3-Aminopropyl)phenyl)pentanamide was prepared following the methodused in Example 111.

Step 1: Sonogashira coupling of bromide 57 with pent-4-ynamide gavetert-butyl 3-(3-(5-amino-5-oxopent-1-ynyl)phenyl)propylcarbamate. Yield(0.967 g, crude). ¹H NMR (400 MHz, CDCl₃) δ 7.64-7.70 (m, 1H), 7.47 (d,J=6.4 Hz, 1H), 7.18 (s, 1H), 7.10 (d, J=6.4 Hz, 1H), 5.60-5.80 (m, 2H),4.53 (bs, 1H), 3.10-3.18 (m, 2H), 2.75 (d, J=7.2 Hz, 2H), 2.60 (t, J=7.6Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 1.76-1.80 (m, 2H), 1.44 (s, 9H).

Step 2: Reduction of 5-(3-(3-Aminopropyl)phenyl)pent-4-ynamide gavetert-butyl 3-(3-(5-amino-5-oxopentyl)phenyl)propylcarbamate as yellowoil. Yield (0.310 g, 83%): MS: 335 [M+1]. The compound was pure enoughto be utilized for the next transformation.

Step 3: BOC deprotection of tert-butyl 3-(3-(5-amino-5-oxopentyl)phenyl)propylcarbamate gave Example 112 as off-white solid. Yield (0.08 g,38%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.19 (m, 1H), 6.97-7.0 (m, 3H),2.50-2.60 (m, 6H), 2.05 (t, J=6.8 Hz, 2H), 1.60-1.70 (m, 2H), 1.43-1.55(m, 4H). ¹³C NMR (100 MHz, DMSO-d₆): 174.2, 142.0, 141.9, 128.3, 128.1,125.6, 40.7, 34.9, 34.0, 32.4, 30.7, 24.8. MS: 235 [M+1]⁺.

Example 113 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenyl)-3-ethylpentan-3-ol

1-(3-(3-Amino-1-hydroxypropyl)phenyl)-3-ethylpentan-3-ol was preparedfollowing the method used in Example 63.

Step 1: Sonogashira coupling of bromide 43 with 3-ethylpent-1-yn-3-olgaveN-(3-(3-(3-ethyl-3-hydroxypent-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide.Yield (0.825 g, 77%). ¹H NMR (400 MHz, CDCl₃) δ 7.41 (s, 1H), 7.28-7.39(m, 3H), 4.83-4.87 (m, 1H), 3.66-3.73 (m, 1H), 3.37-3.44 (m, 1H),1.90-2.02 (m, 2H), 1.70-1.81 (m, 4H), 1.10 (t, J=7.4 Hz, 6H).

Step 2: DeprotectionofN-(3-(3-(3-ethyl-3-hydroxypent-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidegave 1-(3-(3-amino-1-hydroxypropyl)phenyl) hex-1-yn-3-ol as yellow oil.Yield (0.52 g, 91%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (s, 1H), 7.29-7.33(m, 2H), 7.26 (d, J=6.4 Hz, 1H), 4.68 (t, J=4.8 Hz, 1H), 2.74-2.82 (m,2H), 1.76-1.82 (m, 2H), 1.60-1.69 (m, 4H), 0.99 (t, J=7.4 Hz, 6H). ¹³CNMR (100 MHz, DMSO-d₆): 146.5, 130.1, 128.9, 126.0, 125.0, 123.0, 100.0,94.0, 83.3, 75.0, 71.0, 70.2, 34.5, 9.2. ESI MS m/z 262 [M+1]⁺.

Step 3: Reduction of1-(3-(3-amino-1-hydroxypropyl)phenyl)-3-ethylpent-1-yn-3-ol gave Example113 as yellow oil. Yield (0.15 g, 49%). ¹H NMR (400 MHz, DMSO-d₆) δ7.17-7.21 (m, 1H), 7.14 (s, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.02 (d, J=7.2Hz, 1H), 4.60-4.64 (m, 1H), 2.58 (t, J=7.2 Hz, 2H), 2.42-2.50 (m, 2H),1.60-1.68 (m, 2H), 1.50-1.56 (m, 2H), 1.37 (q, J=7.6 Hz, 4H), 0.81 (t,J=7.6 Hz, 6H). ¹³C NMR (100 MHz, DMSO-d₆): 146.5, 142.7, 127.9, 126.4,125.4, 122.9, 72.4, 71.3, 42.0, 40.1, 38.8, 30.4, 29.6, 7.9. MS: 266[M+1]

Example 114 Preparation of2-(3-(2-(tetrahydro-2h-pyran-2-yl)ethyl)phenoxy)ethanamine

2-(3-(2-Tetrahydro-2H-pyran-2-yl)ethyl)phenoxy)ethanamine was preparedfollowing the method used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with2-ethynyltetrahydro-2H-pyran gave2,2,2-trifluoro-N-(2-(3-((tetrahydro-2H-pyran-2-yl)ethynyl)phenoxy)ethyl)acetamide as a brown oil. Yield (0.753 g, 79%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.26-7.32 (m, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.95-6.98 (m, 2H),4.50-4.53 (m, 1H), 4.11 (t, J=5.4 Hz, 2H), 3.83-3.90 (m, 1H), 3.54-3.58(m, 2H), 3.46-3.53 (m, 1H), 1.78-1.86 (m, 2H). 1.46-1.66 (m, 4H).

Step 2: The reduction of2,2,2-trifluoro-N-(2-(3-((tetrahydro-2H-pyran-2-yl)ethynyl)phenoxy)ethyl)acetamideafforded2,2,2-trifluoro-N-(2-(3-(2-(tetrahydro-2H-pyran-2-yl)ethyl)phenoxy)ethyl)acetamideas brown oil. Yield (0.315 g, 77%): ¹H NMR (400 MHz, DMSO-d₆) δ7.15-7.20 (m, 1H), 6.72-6.78 (m, 3H), 4.07 (t, J=5.6 Hz, 2H), 3.86-3.90(m, 1H), 3.52-3.58 (m, 2H), 3.26-3.30 (m, 1H), 3.12-3.18 (m, 1H),2.51-2.68 (m, 2H), 1.52-1.78 (m, 4H), 1.38-1.48 (m, 4H),

Step 3: Deprotection of2,2,2-trifluoro-N-(2-(3-(2-(tetrahydro-2H-pyran-2-yl)ethyl)phenoxy)ethyl)acetamidegave Example 114 as yellow oil. Yield (0.141 g, 63%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.19-7.23 (m, 1H), 6.77-6.82 (m, 3H), 4.10 (t, J=5.2 Hz, 2H),3.83-3.86 (m, 1H), 3.24-3.30 (m, 1H), 3.12-3.20 (m, 3H), 2.50-2.70 (m,2H), 1.50-1.74 (m, 4H), 1.36-1.46 (m, 3H), 1.10-1.20 (m, 1H). ¹³C NMR(100 MHz, DMSO-d₆) δ 158.4, 144.3, 129.3, 121.6, 115.0, 112.4, 76.6,67.9, 64.5, 38.7, 38.2, 31.9, 31.6, 26.2, 23.5. MS: 250 [M+1]⁺.

Example 115 Preparation of1-(3-(3-amino-1-hydroxypropyl)phenethyl)cyclopentanol

1-(3-(3-Amino-1-hydroxypropyl)phenethyl)cyclopentanol was preparedfollowing the method used in Example 19.

Step 1: Sonogashira reaction of bromide 43 with 1-ethynylcyclopentanolyielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1-hydroxycyclopentyl)ethynyl)phenyl)propyl)-acetamideas brown oil. Yield (0.55 g, 55%): ¹H NMR (400 MHz, CDCl₃) δ 7.41 (s,1H), 7.28-7.35 (m, 3H), 4.85-4.87 (m, 1H), 3.66-3.70 (m, 1H), 3.38-3.44(m, 1H), 2.41 (bs, 1H), 1.76-2.08 (m, 10H).

Step 2: Reduction of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1-hydroxycyclopentyl)ethynyl)phenyl)propyl)acetamide gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-(1-hydroxycyclopentyl)ethyl)phenyl)propyl)acetamideas yellow oil. Yield (0.248 g, 62%). ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.31(m, 1H), 7.20 (s, 1H), 7.14-7.18 (m, 2H), 4.86-4.90 (m, 1H), 3.68-3.73(m, 1H), 3.38-3.46 (m, 1H), 2.76-2.80 (m, 2H), 2.25 (s, 1H), 1.96-2.02(m, 3H), 1.80-1.90 (m, 4H), 1.60-1.72 (m, 5H).

Step 3: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-(1-hydroxycyclopentyl)ethyl)phenyl)propyl)acetamidegave Example 115 as yellow oil. Yield (0.12 g, 68%). ¹H NMR (400 MHz,CDCl₃) δ 7.20-7.24 (m, 1H), 7.13 (s, 1H), 7.06-7.11 (m, 2H), 4.61 (t,J=6.4 Hz, 1H), 2.78-2.92 (m, 2H), 2.60-2.65 (m, 2H), 1.80-1.87 (m, 2H),1.64-1.74 (m, 4H), 1.40-1.60 (m, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ145.9, 143.4, 128.5, 127.3, 125.8, 123.2, 80.6, 70.6, 44.1, 38.6, 37.4,31.3, 24.0. MS: 264 [M+1]

Example 116 Preparation of3-(3-(3-aminopropyl)phenyl)-1-phenylpropan-1-ol

3-(3-(3-Aminopropyl)phenyl)-1-phenylpropan-1-ol was prepared followingthe method used in Example 103.

Step 1: Sonogashira reaction of bromide 10 with 1-phenylprop-2-yn-1-olgave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-phenylprop-1-ynyl)phenyl)propyl)acetamideas brown oil. Yield (0.408 g, 80%). This compound was utilized as suchfor the next transformation.

Step 2: Reduction of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-phenylprop-1-ynyl)phenyl)propyl)acetamideyielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-phenylpropyl)phenyl)propyl)acetamideas yellow oil. Yield (0.365 g, 91%). This compound was utilized as suchfor the next transformation.

Step 3: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-phenylpropyl)phenyl)propyl)acetamideand subsequent purification by flash chromatography (0-10% MeOH—NH₃(9.5:0.5)-DCM gradient) gave Example 116 as pale yellow oil. Yield (0.20g, 74%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.30-7.33 (m, 4H), 7.20-7.25 (m,2H), 7.13 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 5.28(d, J=4.4 Hz, 1H), 4.62 (t, J=7.2 Hz, 1H), 4.52-4.63 (m, 1H), 2.79-2.87(m, 2H), 2.50-2.59 (m, 2H), 1.79-1.89 (m, 4H). ¹³C NMR (100 MHz,DMSO-d₆) δ 146.6, 145.7, 142.4, 128.6, 128.5, 127.4, 127.1, 126.2,125.9, 123.4, 72.2, 70.3, 41.6, 37.1, 32.1. MS: 286 [M+1]⁺.

Example 117 Preparation of3-(3-(3-aminopropyl)phenyl)-2,2-dimethylpropyl acetate

3-(3-(3-Aminopropyl)phenyl)-2,2-dimethylpropyl acetate was preparedfollowing the method shown in Scheme 19.

Step 1: Alkylation of 3-bromobenzylbromide (92) with ethyl isobutyrate(93) following the method used in Example 44 (except that saturatedaqueous ammonium chloride was used to quench the reaction instead ofwater), followed by flash chromatography (0-20% EtOAc/hexanes gradient)gave the ester 94 as a light yellow oil. Yield (2.9 g, 87%): ¹H NMR (400MHz, CDCl₃) δ 7.31-7.35 (m, 1H), 7.27 (t, J=2.0 Hz, 1H), 7.11 (t, J=7.6Hz, 1H), 7.01-7.05 (m, 1H), 4.11 (q, J=7.2 Hz, 2H), 2.80 (s, 2H), 1.23(t, J=7.2 Hz, 3H), 1.67 (s, 6H).

Step 2: DIBALH (8.8 mL of a 1.0 M solution in THF, 8.8 mmol) was addedto a stirring solution of the ester 94 (2.1 g, 7.36 mmol) in toluene at0° C. under argon. After 1 h, a second aliquot of DIBALH (4.2 mL, 4.2mmol) was added. After overnight stirring the reaction was quenched withsaturated aqueous ammonium chloride, diluted with 1M HCl, and extractedwith ethyl acetate. Combined organic layers were washed with more 1MHCl, water, saturated aqueous sodium bicarbonate and brine, dried oversodium sulfate, filtered, and concentrated, giving the alcohol 95 as acolorless oil, Yield (1.84 g, quantitative): ¹H NMR (400 MHz, CDCl₃) δ7.30-7.35 (m, 2H), 7.13 (t, J=7.6 Hz, 1H), 7.06-7.10 (m, 1H), 3.29 (d,J=4.8 Hz, 2H), 2.54 (s, 2H), 1.38-1.40 m, 1H), 0.87 (s, 6H).

Step 3: A solution of tri-t-butyl phospine (0.13 mL of a 1M solution indioxane, 0.13 mmol) was added to a degassed mixture ofbis-chloro-triphenylphosphine palladium (49 mg, 0.07 mmol), copperiodide (4.9 mg, 0.026 mmol), di-isopropylamine (0.31 mL, 2.2 mmol),alcohol 95 (0.422 g, 1.73 mmol), and tert-butyl prop-2-ynylcarbamate(0.4 g, 2.6 mmol) in anhydrous dioxane (20 mL). The reaction was heatedto 50° C. overnight, filtered, and purified by flash chromatography(4-60% EtOAc/hexanes gradient), giving alkyne 96 as a yellow oil. Yield(0.162 g, 29%): ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.27 (m, 1H), 7.17-7.23(m, 2H), 7.09-7.13 (m, 1H), 4.74 (brs, 1H), 4.10-4.15 (m, 2H), 3.29 (s,2H), 2.54 (s, 2H), 1.45 (s, 10H), 0.88 (s, 6H).

Step 4: Reduction of the alkyne 96 following the method used in Example2 exept that n-butanol was used as the solvent, followed by flashchromatography (10-60% ethyl acetate/hexanes gradient), gave the alkane97 as a colorless oil. Yield (0.1 g, 63%): ¹H NMR (400 MHz, CDCl₃) δ7.17 (t, J=7.6 Hz, 1H), 6.95-7.02 (m, 3H), 4.53 (m, 1H), 3.27 (s, 2H),3.05-3.15 (m, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.54 (s, 2H), 2.08 (s, 1H),1.57-1.82 (m, 2H), 1.44 (s, 9H), 0.87 (s, 6H).

Step 5: HCl (0.25 mL of a 6.95 M solution in ethanol, 1.74 mmol) wasadded to a solution of alcohol 97 in ethyl acetate (2 mL). The reactionwas stirred overnight, concentrated under reduced pressure, and theresidue extracted from saturated aqueous sodium bicarbonate with ethylacetate. Combined organic layers were washed with water and brine, driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography (5% (7 Nammonia/methanol)/ethyl acetate), giving Example 117 as a colorless oil.Yield (0.035 g, %): ¹H NMR (400 MHz, CDCl₃) δ 7.16 (t, J=8.0 Hz, 1H),6.99-7.04 (m, 1H), 6.89-6.93 (m, 2H), 3.74 (s, 2H), 2.70 (t, J=7.2 Hz,2H), 2.61 (t, J=8.0 Hz, 2H), 2.54 (s, 2H), 2.09 (s, 3H), 1.69-1.78 (m,2H), 1.27 (brs, 2H), 0.89 (s, 6H). ESI MS m/z 264.3 [m+H]⁺

Example 118 Preparation of3-(3-(3-aminopropyl)phenyl)-2,2-dimethylpropan-1-ol

3-(3-(3-Aminopropyl)phenyl)-2,2-dimethylpropan-1-ol was preparedfollowing the method shown in Scheme 20.

Step 1: To a solution of aryl bromide 98 (0.63 g, 2.6 mmol) inacetonitrile (5 mL) was added allyl phthalimide (0.58 g, 3.1 mmol),tri-o-tolyl phosphine (0.079 g, 0.26 mmol), and palladium acetate (0.036g, 0.16 mmol). The mixture was evacuated and purged with argon threetimes, then triethylamine (0.51 mL, 3.65 mmol), was added and theevacuation—purge procedure was repeated three times. The reaction washeated at reflux overnight, then diluted with aqueous NH₄OAc andextracted with EtOAc. The combined organics were washed with water,aqueous NH₄OAc, saturated aqueous NaHCO₃ and brine, then dried overMgSO₄, filtered and concentrated. Flash chromatography of the residue(5-60% EtOAc/Hexanes gradient) gave the alcohol 99 as a white solid.Yield (0.58 g, 64%). ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.88 (m, 2H),7.66-7.72 (m, 2H), 7.10-7.22 (m, 3H), 7.0-7.04 (m, 1H), 6.62 (d, J=16Hz, 1H), 6.18-6.26 (m, 1H), 4.42 (dd, J=1.6, 6.8 Hz, 2H), 3.27 (s, 2H),2.52 (s, 2H), 1.59 (brs, 1H), 0.85 (s, 6H).

Step 2: Reduction of alkene 99 following the method used in Example 117,followed by flash chromatography (20-50% ethyl acetate/hexanes gradient)gave alkane 100 as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.79-7.85(m, 2H), 7.66-7.72 (m, 2H), 7.15 (t, J=7.6 Hz, 1H), 7.0-7.05 (m, 2H),6.92-6.96 (m, 1H), 3.72 (t, J=7.2 Hz, 2H), 3.29 (s, 2H), 2.66 (t, J=7.2Hz, 2H), 2.53 (s, 2H), 1.59-2.05 (m, 2H), 1.54 (s, 1H), 0.87 (s, 6H).

Step 3: Deprotection of alkane 100 following the method used in Example9, followed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetate)gradient), gave Example 118 as a colorless oil. Yield (0.068 g, 33%):7.13-7.18 (m, 1H), 6.94-7.02 (m, 3H), 3.25 (s, 2H), 2.69 (t, J=6.8 Hz,2H), 2.61 (t, 7.6 Hz, 2H), 2.53 (s, 2H), 1.89 (brs, 3H), 1.75 (quint,J=7.2 Hz, 2H), 0.85 (s, 6H). ESI MS m/z 222.2 [m+H]⁺.

Example 119 Prepartion of 2-(3-(3-aminopropyl)phenyl)decan-2-ol

2-(3-(3-Aminopropyl)phenyl)decan-2-ol was prepared following the methodshown in Scheme 21.

Step 1: To a solution of 1-(3-bromophenyl)ethanone (101) (2.0 mL, 15mmol) in anhydrous THF (10 mL) under argon at −78° C. was addedoctylmagnesium bromide. The reaction was allowed to warm to roomtemperature and stirred overnight. The reaction solution was decantedinto saturated aqueous ammonium chloride and stirred for 20 min. Theaqueous was extracted with ethyl acetate and the combined organicswashed with water, saturated aqueous sodium bicarbonate and brine, driedover MgSO4, filtered through celite and concentrated under reducedpressure. Flash chromatography of the residue gave the benzyl hydroxide102 as a colorless oil. Yield (2.7 g, 57%): ¹H NMR (400 MHz, CDCl₃) δ7.59 (t, 2.0 Hz, 1H), 7.30-7.37 (m, 2H), 7.19 (t, J=8.0 Hz, 1H),1.68-1.82 (m, 2H), 1.64 (brs, 1H), 1.52 (s, 3H), 1.18-1.30 (m, 11H),1.0-1.16 (m, 1H), 0.85 (t, J=7.2 Hz, 3H).

Step 2: Heck coupling of bromide 102 with allyl phthalimide followingthe method used in Example 118, followed by chromatography (5-40% ethylacetate/hexanes gradient), gave the alkene 103 as a yellow oil. Yield(0.67 g, 84%): ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.88 (m, 2H), 7.66-7.74(m, 2H), 7.39-7.42 (m, 1H), 7.20-7.28 (m, 3H), 6.63-6.69 (m, 1H), 6.26(dt, J=6.4, 15.6 Hz, 1H), 4.44 (dd, 1.2, 6.0 Hz, 2H), 1.70-1.80 (m, 2H),1.62 (brs, 1H), 1.51 (s, 3H), 1.30-1.60 (m, 12H), 0.84 (t, J=3.2 Hz,3H).

Step 3: Reduction of alkene 103 following the method used in Example117, followed by flash chromatography (0-40% ethyl acetate/hexanesgradient) gave alkane 104 as a colorless oil. Yield (0.43 g, 65%): ¹HNMR (400 MHz, CDCl₃) δ 7.79-7.85 (m, 2H), 7.68-7.72 (m, 2H), 7.16-7.28(m, 3H), 7.04-7.07 (m, 1H), 3.73 (t, J=7.2 Hz, 2H), 2.69 (t, J=8.0 Hz,2H), 1.99-2.10 (m, 2H), 1.65-1.70 (m, 3H), 1.52 (s, 3H), 1.05-1.30 (m,12), 0.83 (t, J=7.2 Hz, 3H).

Step 4: Deprotection of alkane 104 following the method used in Example9, followed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetate)gradient gave Example 119 as a colorless oil. Yield (0.068 g, 25%): ¹HNMR (400 MHz, CDCl₃) δ 7.21-7.27 (m, 3H), 7.03-7.07 (m, 1H), 2.74 (t,J=6.8 Hz, 2H), 2.66 (t, 8.0 Hz, 2H), 1.72-1.83 (m, 4H), 1.53 m, 6H),1.06-1.30 (m, 12H), 0.85 (t, J=7.2 Hz, 3H). ESI MS m/z 292.4 [m+H]⁺,274.4 [m+H−H₂O].

Example 120 Preparation of 2-(3-(3-aminopropyl)phenyl)hexan-2-ol

2-(3-(3-Aminopropyl)phenyl)hexan-2-ol was prepared following the methodused in Example 119.

Step 1: Grignard coupling of butylmagnesium chloride with1-(3-bromophenyl)ethanone followed by flash chromatography (0-25% ethylacetate/hexanes gradient), gave 2-(3-bromophenyl)hexan-2-ol as a yellowoil. Yield (0.99 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ 7.59 (t, J=2.0 Hz,1H), 7.30-7.37 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 1.70-1.84 (m, 2H), 1.52(s, 3H), 1.64 (brs, 1H), 1.18-1.30 (m, 3H), 1.02-1.14 (m, 1H), 0.84 (t,J=7.2 Hz, 3H).

Step 2: Heck coupling of 2-(3-bromophenyl)hexan-2-ol with allylphthalimide, followed by chromatography (5-30% ethyl acetate/hexanesgradient), gave(E)-2-(3-(3-(2-hydroxyhexan-2-yl)phenyl)allyl)isoindoline-1,3-dione as acolorless oil. Yield (0.46 g, 47%): ¹H NMR (400 MHz, CDCl₃) δ 7.78-7.86(m, 2H), 7.66-7.72 (m, 2H), 7.40 (s, 1H), 7.18-7.28 (m, 3H), 6.61-6.68(m, 1H), 6.24 (dt, J=6.4, 15.6 Hz, 1H), 4.42 (dd, J=1.2, 6.4 Hz, 2H),1.85 (brs, 1H), 1.54-1.56 (m, 2H), 1.50 (s, 3H), 1.15-1.30 (m, 3H),1.00-1.10 (m, 1H), 0.75-0.85 (m, 3H).

Step 3: Reduction of(E)-2-(3-(3-(2-hydroxyhexan-2-yl)phenyl)allyl)isoindoline-1,3-dione,followed by flash chromatography (0-40% ethyl acetate/hexanes gradient)gave 2-(3-(3-(2-hydroxyhexan-2-yl)phenyl)propyl)isoindoline-1,3-dione asa colorless oil. Yield (0.43 g, 65%): ¹H NMR (400 MHz, CDCl₃) δ7.80-7.84 (m, 2H), 7.68-7.72 (m, 2 h), 7.27 (brs, 1H), 7.16-7.23 (m,2H), 7.04-7.08 (m, 1H), 3.73 (t, J=7.2 Hz, 2H), 2.69 (t, J=8.0 Hz, 2H),2.03 (quint, J=7.6 Hz, 2H), 1.54-1.56 (m, 2H), 1.65 (brs, 1H), 1.52 (s,3H), 1.15-1.30 (m, 3H), 1.10-1.30 (m, 1H), 0.83 (t, J=7.2 Hz, 3H).

Step 4: Deprotection of2-(3-(3-(2-hydroxyhexan-2-yl)phenyl)propyl)isoindoline-1,3-dionefollowed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetategradient), gave Example 120 a colorless oil. Yield (0.157 g, 90%): ¹HNMR (400 MHz, CDCl₃) δ 7.20-7.27 (m, 3H), 7.03-7.07 (m, 1H), 2.73 (t,J=7.2 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 1.70-1.84 (m, 4H), 1.53 (s, 3H),1.42 (brs, 3H), 1.18-1.30 (m, 3H), 1.06-1.16 (m, 1H), 0.84 (t, J=7.2 Hz,3H). ESI MS m/z 236.2 [m+H]⁺, 218.2 [m+H−H₂O].

Example 121 Preparation of1-(3-(3-aminopropyl)phenyl)-2-methylhexan-2-ol

1-(3-(3-Aminopropyl)phenyl)-2-methylhexan-2-ol was prepared followingthe method used in Example 119.

Step 1: Grignard coupling of n-butylmagnesium chloride with1-(3-bromophenyl)propan-2-one, followed by flash chromatography (0-25%ethyl acetate/hexanes gradient), gave1-(3-bromophenyl)-2-methylhexan-2-ol as a yellow oil. Yield (0.99 g,51%): ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.38 (m, 2H), 7.11-7.19 (m, 2H),2.70 (dd, J=13.4, 28.8 Hz, 2H), 1.24-1.48 (m, 7H), 1.13 (s, 3H), 0.91(t, J=7.2 Hz, 3H).

Step 2: Heck coupling of 1-(3-bromophenyl)-2-methylhexan-2-ol with allylphthalimide, followed by chromatography (5-30% ethyl acetate/hexanesgradient), gave(E)-2-(3-(3-(2-hydroxy-2-methylhexyl)phenyl)allyl)isoindoline-1,3-dioneas a white solid. Yield (0.55 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ7.80-7.88 (m, 2H), 7.68-7.74 (m, 2H), 7.16-7.26 (m, 3H), 7.04-7.08 (m,1H), 6.60-6.66 (m, 1H), 6.24 (dt, J=6.4, 16 Hz, 1H), 4.43 (dd, J=1.2,6.4 Hz, 2H), 2.69 (dd, J=13.2, 28 Hz, 2H), 1.30-1.50 (m, 7H), 1.10 (s,3H), 0.89 (t, J=7.2 Hz, 3H).

Step 3: Reduction of(E)-2-(3-(3-(2-hydroxy-2-methylhexyl)phenyl)allyl)isoindoline-1,3-dione,followed by flash chromatography (0-40% ethyl acetate/hexanes gradient)gave2-(3-(3-(2-hydroxy-2-methylhexyl)phenyl)propyl)isoindoline-1,3-dione asa colorless oil. Yield (0.43 g, 65%): ¹H NMR (400 MHz, CDCl₃) δ7.78-7.84 (m, 2H), 7.66-7.72 (m, 2H), 7.16 (t, J=8.0 Hz, 1H), 7.04-7.08(m, 2H), 6.95-6.99 (m, 1H), 3.72 (t, J=7.2 Hz, 2H), 2.62-2.76 (m, 4H),2.03 (quint, J=7.6 Hz, 2H), 1.25-1.50 (m, 7H), 1.12 (s, 3H), 0.91 (t,J=7.2 Hz, 3H).

Step 4: Deprotection of2-(3-(3-(2-hydroxy-2-methylhexyl)phenyl)propyl)isoindoline-1,3-dionefollowed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetate)gradient gave Example 121 a colorless oil. Yield (0.144 g, 85%): ¹H NMR(400 MHz, CDCl₃) δ 7.18-7.24 (m, 1H), 7.00-7.08 (m, 3H), 2.68-2.78 (m,4H), 2.60-2.68 (m, 2H), 1.71-1.80 (m, 2H), 1.24-1.50 (m, 9H), 1.12 (s,3H), 0.91 (t, J=7.2 Hz, 3H). ESI MS m/z 250.3 [m+H]⁺, 232.3 [m+H−H₂O]

Example 122 Preparation of 3-(3-(4-methoxybutyl)phenyl)propan-1-amine

3-(3-(4-Methoxybutyl)phenyl)propan-1-amine was prepared following themethod used in Example 76.

Step 1: Sonogashira reaction of bromide 57 with 4-methoxybut-1-yne gavetert-butyl 3-(3-(4-methoxybut-1-ynyl)phenyl)propylcarbamate as yellowoil. Yield (0.83 g, 77%): ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.25 (m, 2H),7.16-7.21 (m, 1H), 7.09 (d, J=7.6 Hz, 1H), 4.51 (bs, 1H), 3.60 (t, J=7.8Hz, 2H), 3.41 (s, 3H), 3.10-3.16 (m, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.59(t, J=7.6 Hz, 2H), 1.76-1.84 (m, 2H), 1.44 (s, 9H).

Step 2: Reduction of tert-butyl 3-(3-(4-methoxybut-1-ynyl)phenyl)propylcarbamate gave tert-butyl 3-(3-(4-methoxybutyl)phenyl)propylcarbamate asyellow oil. Yield (0.81 g, 83%): ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.20 (m,1H), 6.97-7.02 (m, 3H), 4.53 (bs, 1H), 3.39 (t, J=6.4 Hz, 2H), 3.32 (s,3H), 3.10-3.17 (m, 2H), 2.58-2.64 (m, 4H), 1.76-1.84 (m, 2H), 1.59-1.70(m, 4H), 1.44 (s, 9H).

Step 3: BOC deprotection of tert-butyl 3-(3-(4-methoxybutyl)phenyl)propylcarbamate gave Example 122 hydrochloride as an off-white solid.Yield (0.615 g, 96%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.16-7.19 (m, 1H),6.99-7.02 (m, 3H), 3.29 (t, J=6.2 Hz, 2H), 3.18 (s, 3H), 2.76 (t, J=7.6Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 2.54 (t, J=7.4 Hz, 2H), 1.77-1.83 (m,2H), 1.50-1.59 (m, 2H), 1.44-1.49 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ142.7, 141.3, 128.8, 128.7, 126.4, 126.1, 72.1, 58.3, 38.8, 35.3, 32.3,29.2, 29.1, 28.1. MS: 222 [M+1]

Example 123 Preparation of3-(3-(2-aminoethoxy)phenyl)-1-phenylpropan-1-ol

3-(3-(2-Aminoethoxy)phenyl)-1-phenylpropan-1-ol was prepared followingthe method used in Example 64.

Step 1: Sonogashira reaction of bromide 19 with 1-phenylprop-2-yn-1-olgave2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-phenylprop-1-ynyl)phenoxy)ethyl)acetamideas a brown oil. Yield (0.55 g, 47%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.61(d, J=7.2 Hz, 1H), 7.30-7.41 (m, 5H), 7.13-7.16 (m, 1H), 7.06 (s, 1H),6.89 (dd, J=8.4, 2.4 Hz, 1H), 5.69 (d, J=6.0 Hz, 1H), 4.10 (t, J=5.2 Hz,2H), 3.77-3.81 (m, 2H), 2.26 (d, J=6.0 Hz, 1H).

Step 2: The reduction of2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-phenylprop-1-ynyl)phenoxy)ethyl)acetamidegave2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-phenylpropyl)phenoxy)ethyl)acetamideas yellow oil. Yield (0.45 g, 80%). MS: 366 [M−1].

Step 3: Deprotection of2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-phenylpropyl)phenoxy)ethyl)acetamidegave Example 123 as off-white semi-solid. Yield (0.233 g, 73%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.31-7.35 (m, 4H), 7.20-7.27 (m, 1H), 7.14-7.19 (m,1H), 6.71-6.75 (m, 3H), 5.25 (d, J=4.4 Hz, 1H), 4.49-4.54 (m, 1H), 3.87(t, J=5.8 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.50-2.66 (m, 2H), 1.820-1.90(m, 2H), 1.52-1.60 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.2, 146.6,144.1, 129.7, 128.5, 127.1, 126.3, 120.9, 114.9, 112.1, 72.1, 70.4,41.5, 41.4, 40.6, 32.1. MS: 272 [M+1]⁺

Example 124 Preparation of3-amino-1-(3-(3-hydroxy-3-phenylpropyl)phenyl)propan-1-ol

3-Amino-1-(3-(3-hydroxy-3-phenylpropyl)phenyl)propan-1-ol was preparedfollowing the method used in Example 19.

Step 1: Sonogashira reaction of 43 with 1-phenylprop-2-yn-1-ol gave2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-phenylprop-1-ynyl)phenyl)propyl)acetamideas brown oil. Yield (0.408 g, 80%). This compound was utilized as suchfor the next transformation.

Step 2: Reduction of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-phenylprop-1-ynyl)phenyl)propyl)acetamideyielded2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-phenylpropyl)phenyl)propyl)acetamideas yellow oil. Yield (0.365 g, 91%). This compound was utilized as suchfor the next transformation.

Step 3: Deprotection of2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-phenylpropyl)phenyl)propyl)acetamideand subsequent purification by flash chromatography (0-10% MeOH—NH₃(9.5:0.5)-DCM gradient) gave Example 124 as pale yellow oil. Yield (0.20g, 74%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.30-7.33 (m, 4H), 7.20-7.25 (m,2H), 7.13 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 5.28(d, J=4.4 Hz, 1H), 4.62 (t, J=7.2 Hz, 1H), 4.52-4.63 (m, 1H), 2.79-2.87(m, 2H), 2.50-2.59 (m, 2H), 1.79-1.89 (m, 4H). ¹³C NMR (100 MHz,DMSO-d₆) δ 146.6, 145.7, 142.4, 128.6, 128.5, 127.4, 127.1, 126.2,125.9, 123.4, 72.2, 70.3, 41.6, 37.1, 32.1. MS: 286 [M+1]⁺.

Example 125 Preparation of 3-(3-(2-aminoethoxy)phenyl)propan-1-ol

3-(3-(2-Aminoethoxy)phenyl)propan-1-ol was prepared following the methodused in Example 64.

Step 1: Sonogashira reaction of bromide 19 with propargyl alcohol gave2,2,2-trifluoro-N-(2-(3-(3-hydroxyprop-1-ynyl)phenoxy)ethyl)acetamide asa brown oil. Yield (1.0 g, 43%). The crude material was directlyutilized in the next step.

Step 2: The reduction of2,2,2-trifluoro-N-(2-(3-(3-hydroxyprop-1-ynyl)phenoxy)ethyl)acetamidegave 2,2,2-trifluoro-N-(2-(3-(3-hydroxypropyl) phenoxy)ethyl)acetamideas yellow oil. Yield (0.563 g, 91%). MS: 290 [M−1].

Step 3: Deprotection of 2,2,2-trifluoro-N-(2-(3-(3-hydroxypropyl)phenoxy)ethyl)acetamide gave Example 125 as a yellow oil. Yield (0.21 g,56%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.19 (m, 1H), 6.72-6.77 (m, 3H),3.94 (t, J=5.6 Hz, 2H), 3.38 (t, J=6.4 Hz, 2H), 2.91 (t, J=5.6 Hz, 2H),2.55 (t, J=7.8 Hz, 2H), 1.64-1.72 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ158.5, 143.8, 129.2, 120.7, 114.6, 111.6, 68.3, 60.1, 40.1, 34.2, 31.7.MS: 210 [M+1]⁺.

Example 126 Preparation of5-(3-(3-aminopropyl)phenyl)-N,N-dimethylpentanamide

5-(3-(3-Aminopropyl)phenyl)-N,N-dimethylpentanamide was preparedfollowing the method used in Example 76.

Step 1: Sonogashira coupling of bromide 57 withN,N-dimethylpent-4-ynamide gave tert-butyl3-(3-(5-(methylamino)-5-oxopent-1-ynyl)phenyl)propyl carbamate. Yield(1.10 g, crude).

Step 2: Reduction of tert-butyl3-(3-(5-(dimethylamino)-5-oxopent-1-ynyl)phenyl)propylcarbamate gavetert-butyl 3-(3-(5-(dimethylamino)-5-oxopentyl)phenyl)propylcarbamate asyellow oil. Yield (0.2 g, 96%): ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.20 (m,1H), 6.97-7.01 (m, 3H), 4.59 (bs, 1H), 3.10-3.17 (m, 2H), 2.98 (s, 3H),2.88 (s, 3H), 2.58-2.64 (m, 4H), 2.32 (t, J=6.6 Hz, 2H), 1.52-1.78 (m,6H), 1.44 (s, 9H).

Step 3: BOC deprotection of tert-butyl3-(3-(5-(dimethylamino)-5-oxopentyl)phenyl)propylcarbamate gave5-(3-(3-aminopropyl)phenyl)-N,N-dimethyl pentanamide hydrochloride.Neutralization with conc. ammonia followed by purification by flashchromatography ((0-10%) MeOH:DCM gradient) gave Example 126 as yellowoil. Yield (0.09 g, 66%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.13-7.17 (m, 1H),6.96-6.99 (m, 3H), 2.91 (s, 3H), 2.77 (s, 3H), 2.50-2.56 (m, 6H), 2.26(t, J=7.2 Hz, 2H), 1.60-1.66 (m, 6H), 1.43-1.59 (m, 4H). ¹³C NMR (100MHz, DMSO-d₆) δ 172.7, 142.5, 128.7, 128.6, 126.0, 37.2, 35.4, 35.2,33.0, 32.6, 31.1, 24.8. MS: 263 [M+1]⁺.

Example 127 Preparation of 4-(3-(4-aminobutyl)phenethyl)heptan-4-ol

4-(3-(4-Aminobutyl)phenethyl)heptan-4-ol was prepared following themethod Scheme 22.

Step 1: Sonogashira coupling of 3-tetrahydropyranylbromophenol and3-butyn-1-ol following the method used in Example 13 except that thereaction mixture was heated at 90° C. for 18 hr. Flash chromatographypurification (30% to 100% EtOAc-hexanes gradient) gave alcohol 105 anorange oil. Yield (2.46 g, 85%); ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (t,J=8.0 Hz, 1H), 6.93-7.01 (m, 3H), 5.45 (t, J=3.2 Hz, 1H), 4.86 (t, J=5.6Hz, 1H), 3.66-3.75 (m, 1H), 3.48-3.58 (m, 3H), 2.51 (t, J=6.4 Hz, 2H),1.64-1.90 (m, 3H), 1.44-1.64 (m, 3H).

Step 2: Diethyl azodicarboxylate (1.195 g, 6.86 mmol) was added underargon to a stirred solution of alcohol 105 (39 g, 5.64 mmol),phthalimide (0.90 g, 6.12 mmol) and triphenylphosphine (1.64 g, 6.25mmol) in anhydrous THF. The reaction mixture was stirred at roomtemperature for 20 min and concentrated under reduced pressure.Purification by flash chromatography (10% to 40% ethyl acetate/hexanesgradient) gave phthalimide 106 a colorless oil. Yield (1.77 g, 84%); ¹HNMR (400 MHz, CDCl₃) δ 7.82-7.88 (m, 2H), 7.68-7.73 (m, 2H), 7.14 (t,J=8.0 Hz, 1H), 7.02-7.04 (m, 1H), 6.92-6.97 (m, 2H), 5.36 (t, J=3.1 Hz,1H), 3.95 (t, J=7.2 Hz, 2H), 3.87 (ddd, J=3.13, 9.6, 14.5 Hz, 1H), 3.58(dtd, J=1.2, 4.1, 11.2 Hz, 1H), 2.80 (t, J=7.2 Hz, 2H), 1.92-2.05 (m,1H), 1.78-1.85 (m, 2H), 1.52-1.73 (m, 3H)

Step 3. A solution of butynylphthalimide 106 (1.00 g, 2.66 mmol) in EtOH(abs, 50 mL) was degassed by bubbling argon for 3 min. Palladium oncarbon (10%, 0.102 g) was added to the reaction mixture, which wasdegassed by bubbling argon for 30 sec, and then by applying vacuum/H₂three times. The reaction mixture was stirred under hydrogen atmospherefor 45 min and filtered. The filtrate was used directly in the nextstep.

Deprotection with hydrazine monohydrate following the method used inExample 12 except that the reaction mixture was heated at +50 OC for 16hrs, gave 4-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)but-3-yn-1-amine as acolorless oil, which was used in the next step without purification.

Protection of 4-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)but-3-yn-1-aminewith ethyl trifluoroacetate following the method used in Example 19except that the reaction was carried out in THF, gave trifluoroacetamide107 a colorless oil. Yield (0.72 g, 78% after three steps); ¹H NMR (400MHz, DMSO-d₆) δ 9.37 (br.t, 1H), 7.12-7.18 (m, 1H), 6.75-6.83 (m 3H),5.40 (t, J=3.2 Hz, 1H), 3.69-3.77 (m, 1H), 3.47-3.54 (m, 1H), 3.17 (q,J=6.4 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 1.63-1.90 (m, 3H), 1.40-1.62 (m,7H).

Step 4. A mixture of 107 (0.72 g, 2.08 mmol) and p-toluenesulfonic acidmonohydrate (0.366 g) in THF:H₂O (3:1, 20 mL) was stirred at roomtemperature for 3.5 hr. The reaction mixture was partitioned betweenaqueous NaHCO₃-brine solution and EtOAc. Aqueous layer was aextractedwith EtOAc. Combined organic layers were washed with brine andconcentrated under reduced pressure. Purification by flashchromatography (10% to 50% EtOAc-hexanes gradient) gave2,2,2-trifluoro-N-(4-(3-hydroxyphenyl)butyl)acetamide as a colorlessoil. Yield (0.438 g, 96%).

A solution of trifluoromethanesulfonic anhydride (0.32 mL, 1.90 mmol)was added to a stirred solution of2,2,2-trifluoro-N-(4-(3-hydroxyphenyl)butyl)acetamide (0.438 g, 1.68mmol) and diisopropylethylamine (0.5 mL, 2.87 mmol) at 0° C. under argonin anhydrous CH₂Cl₂. The reaction mixture was stirred at 0° C. for 15min and concentrated under reduced pressure. EtOAc was added to theresidue and the mixture was washed with brine, dried over anhydrousMgSO₄, and the filtrate was concentrated under reduced pressure to givecrude triflate 108 a light brown oil which was used in the next stepwithout additional purification. Yield (0.683 g, quant.); ¹H NMR (400MHz, DMSO-d₆) δ 9.38 (brt, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.24-7.34 (m,3H), 3.17 (q, 6.4 Hz, 2H), 2.64 (t, J=7.2 Hz, 2H), 1.40-1.60 (m, 4H).

Step 5. Sonogashira coupling of triflate 108 with 4-ethynylheptan-4-olfollowing the method used in Example 2 except that the reaction was runfor 15 hrs, after flash chromatography purification (5% to 40%EtOAc-hexanes gradient) gave alkynol 109 a light brown oil. Yield (0.327g, 51%); ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (brt, 1H), 7.20-7.34 (m, 1H),7.13-7.18 (m, 2H), 5.10 (s, 1H), 3.17 (q, J=6.4 Hz, 1H), 2.54 (t, J=7.2Hz, 2H), 1.38-1.62 (m, 12H), 0.88 (t, J=7.6 Hz, 6H).

Step 6. Deprotection of trifluoroacetamide 109 following the method usedin Example 19 except that the reaction mixture was stirred at 50° C. for3.5 hr after purification by flash chromatography (10%-100% 7NNH₃/MeOH/CH₂Cl₂— CH₂Cl₂) gave amine 110 a white solid. Yield (0.175 g,71%); ¹H NMR (400 MHz, CD₃OD) δ 7.12-7.24 (m, 4H), 2.46-2.66 (m, 4H),1.42-1.73 (m, 10H), 1.43-1.42 (m, 2H), 0.97 (t, J=7.2 Hz, 6H); ¹³C NMR(100 MHZ, CD₃OD), δ 142.8, 131.3, 128.8, 128.3, 128.2, 123.6, 91.9,83.9, 70.9, 44.5, 41.2, 35.2, 32.2, 28.6, 17.6, 13.6; RP-HPLC t_(R)=7.06min, 92.5% (AUC); LC-MS m/z=288.25 [M+H]⁺.

Step 7. A solution of alkyne 110 (0.0446 g, 0.155 mmol) in EtOAc (5 mL)was degassed by applying vac/argon 2×. Then Pd/C (10%, 0.0166 g) wasadded to the reaction mixture, degassed by applying vac/H₂ 2×, and thereaction mixture was stirred at room temperature for 18 hrs. Filtrationfollowed by flash chromatography purification (10% to 50% of 20% 7NNH₃/MeOH/CH₂Cl₂— CH₂Cl₂ gradient) gave Example 127 as a colorless oil.Yield (0.0321 g, 71%); ¹H NMR (400 MHz, CD₃OD) δ 7.13 (t, J=7.6 Hz, 1H),6.95-7.01 (m, 3H), 2.52-2.67 (m, 6H), 1.58-1.69 (m, 4H), 1.41-1.53 (m,6H), 1.30-1.40 (m, 4H), 0.93 (t, J=7.2 Hz, 6H); RP-HPLC (Method 2)t_(R)=7.06 min, 87.4% (AUC); LC-MS m/z=288.25 [M+H]⁺.

Example 128 Preparation of(1S,2S)-3-amino-1-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diol

(1S,2S)-3-Amino-1-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diolwas prepared following the method shown in Scheme 23

Step 1: To an ice-cold solution of 3-bromobenzaldehyde (30) (3.9 mL,33.30 mmol) in anhydrous dichloromethane (100 mL) was added(carbethoxymethylene)triphenylphosphorane (11.65 g, 33.44 mmol). Thereaction mixture was stirred at 0° C. for 5 min, then allowed to warm toroom temperature over 30 min and concentrated under reduced pressure.The residue was resuspended in 5% EtOAc/hexanes, stirred for 10 min atroom temperature and then filtered. Filter cake was washed with hexanes,and the filtrate was concentrated under reduced pressure. Purificationof the residue by flash column chromatography (silica gel, hexanes to10% EtOAc/hexanes gradient) gave allyl ester 111 a white solid. Yield(7.63 g, 90%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (t, J=1.8 Hz, 1H),7.70-7.72 (m, 1H), 7.59 (d, J=16.4 Hz, 1H), 7.58 (ddd, J=1.0, 2.0, 8.0Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 6.69 (d, J=16.0 Hz, 1H), 4.17 (q, J=7.2Hz, 2H), 1.23 (t, J=7.0 Hz, 3H).

Step 2. A solution of diisobutyl aluminum hydride (DIBAL-H, 60 mL of a1.0 M solution in CH₂Cl₂, 60.0 mmol) was added to an ice-cold solutionof ester 111 (0.63 g, 29.9 mmol) in diethyl ether (100 mL). The reactionmixture was stirred at 0° C. for 30 min after which aqueous solutionofNaHSO₄ (2M, 42 mL) was added and the resulting mixture was stirred for1.5 hrs while warming to room temperature. Anhydrous MgSO₄ was added tothe stirred reaction mixture, and after 30 min the mixture was filteredand the filtrate cake washed excessively with EtOAc. Filtrate wasconcentrated under reduced pressure to give alcohol 112 a colorless oil.Yield (6.42 g, quant.). ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (t, J=1.8 Hz,1H), 7.40 (dt, J=1.2, 7.6 Hz, 1H), 7.38 (ddd, J=1.0, 2.0, 8.0 Hz, 1H),7.25 (t, J=7.6 Hz, 1H), 6.48-6.54 (m, 1H), 6.43 (dt, J=4.3, 16.0 Hz,1H), 4.88 (t, J=5.5 Hz, 1H), 4.08-4.12 (m, 2H).

Step 3. Acetic anhydride (1.2 mL, 12.7 mmol) was added to a stirredsolution of alcohol 112 (2.535 g, 11.90 mmol), Et₃N (2.0 mL, 14.3 mmol)and DMAP (0.141 g, 1.15 mmol) in anhydrous CH₂Cl₂. The reaction mixturewas stirred at room temperature for 30 min and concentrated underreduced pressure. Purification by flash column chromatography (silicagel, 5% to 20% EtOAc/hexanes gradient) gave acetate 113 a colorless oil.Yield (2.71 g, 89%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (t, J=1.8 Hz, 1H),7.40-7.46 (m, 2H), 7.27 (t, J=7.8 Hz, 1H), 6.58-6.65 (m, 1H), 6.42 (dt,J=5.9, 16.0 Hz, 1H), 4.66 (dd, J=1.4, 5.9 Hz, 1H), 2.04 (s, 3H).

Step 4. A mixture of allyl acetate 113 (0.71 g, 10.6 mmol), sodium azide(0.787 g, 12.1 mmol), water (20 mL) and THF (50 mL) was degassed bybubbling argon for 3 min.tris-Dibenzylideneacetonyl-bis-palladium-chloroform adduct (0.158 g,0.17 mmol) and diphenylphosphinoferrocene (0.1773 g, 0.32 mmol) wereadded to the reaction mixture. Air was evacuated by applyingvacuum/argon 3× and then the reaction mixture was heated at 60° C. underargon for 4 hrs. The reaction mixture was concentrated under reducedpressure, water was added to the residue and the product was extractedtwice with hexanes. Combined hexane layers were washed with saturatedbrine, dried with anhydrous MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. Purification of the residue byflash column chromatography (silica gel, 5% to 30% EtOAc/hexanesgradient) gave allyl azide 114 as a colorless oil. Yield (1.90 g, 75%).¹H NMR (400 MHz, DMSO-d₆) δ 7.69 (t, J=1.8 Hz, 1H), 7.42-7.48 (m, 2H),7.28 (t, J=7.8 Hz, 1H), 6.62-6.68 (m, 1H), 6.45 (dt, J=6.3, 15.8 Hz,1H), 4.02 (dd, J=1.2, 6.3 Hz, 1H).

Step 5. To a 100-ml round bottomed flask was placed H₂O (19 mL) andtert-BuOH (19 mL) followed by AD-mix-β (5.61 g). The mixture was stirredat room temperature for 10 min after which MeSO₂NH₂ (0.36 g, 3.79 mmol)was added. The reaction mixture was cooled to 0° C., allyl azide 114(0.90 g, 3.78 mmol) was added and the reaction mixture was stirred at 0°C. for 24 hrs. Na₂S₂O₃ (6.30 g) was added and the mixture was stirredfor another hour after which EtOAc (50 mL) was added followed bysaturated NaCl (50 mL). Layers were separated and aqueous layer wasextracted with EtOAc (3×25 mL). Combined organic layers were washed withbrine (50 mL), dried over anhydrous MgSO₄ and filtered. Filtrate wasconcentrated under reduced pressure and the residue was purified byflash column chromatography (silica gel, 10% to 90% EtOAc/hexanesgradient) to give azido diol 115 as a thick colorless oil. Yield (1.02g, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (t, J=1.6 Hz, 1H), 7.40 (ddd,J=1.2, 2.0, 7.6 Hz, 1H), 7.29-7.33 (m, 1H), 7.25 (t, J=7.6 Hz, 1H), 5.52(d, J=5.1 Hz, 1H), 5.26 (d, J=5.9 Hz, 1H), 4.51 (t, J=4.7 Hz, 1H), 3.15(dd, J=3.3, 12.5 Hz, 1H), 3.02 (dd, J=8.0, 12.7 Hz, 1H).

Step 6. A mixture of azido diol 115 (0.826 g, 3.037 mmol),triphenylphosphine (0.84 g, 3.20 mmol), THF (10 mL), water (0.2 mL) andethyl trifluoroacetate (1 mL) was heated at 50° C. for 5 hrs and thenconcentrated under reduced pressure. Purification of the residue byflash column chromatography (silica gel, 20% to 90% EtOAc/hexanesgradient) gave trifluoroacetamide 116 as white solid. Yield (0.73 g,70%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (t, J=5.3 Hz, 1H), 7.52 (t, J=1.6Hz, 1H), 7.40 (ddd, J=1.2, 2.0, 7.8 Hz, 1H), 7.30-7.33 (m, 1H), 7.25 (t,J=7.6 Hz, 1H), 5.48 (d, J=5.1 Hz, 1H), 5.00 (d, J=5.9 Hz, 1H), 4.51 (t,J=4.7 Hz, 1H), 3.70-3.76 (m, 1H), 3.24 (dt, J=4.9, 13.3 Hz, 1H), 2.98(ddd, J=5.7, 8.8, 13.3 Hz, 1H).

Step 7. A mixture of alkene 116 (0.116 g, 0.922 mmol), bromide 117(0.242 g, 0.708 mmol), tetrabutylammonium acetate (1.19 g) and Pd(OAc)₂(0.029 g, 0.127 mmol) was heated under argon at 90° C. for 5 hrs. Waterand brine were added to the reaction mixture which was extracted threetimes with EtOAc. The combined organic layers were washed with brine,dried over anhydrous MgSO₄ and concentrated under reduced pressure.Purification by flash column chromatography (silica gel, 20% to 70%EtOAc/hexanes gradient) gave alkene 118 as a white foam. Yield (0.2128g, 78%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (t, J=5.3 Hz, 1H), 7.35-7.37(m, 1H), 7.20-7.26 (m, 2H), 7.13-7.18 (m, 1H), 6.51 (d, J=16.2 Hz, 1H),6.33 (d, J=16.0 Hz, 1H), 5.33 (d, J=4.9 Hz, 1H), 4.94 (d, J=5.7 Hz, 1H),4.46 (t, J=4.8 Hz, 1H), 4.41 (s, 1H), 3.70-3.76 (m, 1H), 3.18 (dt,J=4.5, 13.3 Hz, 1H), 2.99 (ddd, J=6.1, 8.8, 14.3 Hz, 1H), 1.54-1.66 (m,2H), 1.36-1.54 (m, 7H), 1.18-1.26 (m, 1H).

Step 8.N-((2S,3S)-2,3-dihydroxy-3-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propyl)-2,2,2-trifluoroacetamide(118) was deprotected according to the method used in Example 19 exceptthat three equivalents of K₂CO₃ were used in a MeOH:H₂O (2:1) mixtureand the reaction mixture was heated at 50° C. for 5 hrs. Following thereaction, reaction mixture was concentrated under reduced pressure,resuspended in EtOAc/EtOH and purified by flash chromatography using agradient of 50% 7N NH₃/MeOH in EtOAc/hexanes to give alkene 119 as acolorless oil. Yield (0.118 g, 74%). ¹H NMR (400 MHz, MeOH-d₄) δ7.42-7.44 (m, 1H), 7.30 (dt, J=1.6, 7.6 Hz, 1H), 7.27 (t, J=7.4 Hz, 1H),7.21 (dt, J=1.6, 7.2 Hz, 1H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (d, J=16.0Hz, 1H), 4.50 (d, J=5.9 Hz, 1H), 3.62-2.70 (m, 1H), 2.51-2.58 (m, 2H),1.66-1.77 (m, 2H), 1.48-1.66 (m, 7H), 1.28-1.40 (m, 1H); ¹³C NMR (100MHz, MeOH-d₄) δ 142.3, 137.9, 137.7, 128.3, 126.7, 125.7, 125.6, 124.6,76.0, 75.8, 71.2, 43.6, 37.5, 25.5, 21.9, 20.9; RP-HPLC (Method 1)t_(R)=4.73 min, 97% (AUC); ESI MS m/z 292.3 [M+H]⁺.

Step 9. A solution of alkene 119 (0.0612 g, 0.21 mmol) in EtOH (abs, 8mL) was degassed by applying vac/argon 2×. Then Pd/C (10%, 0.0139 g) wasadded to the reaction mixture, degassed by applying vac/H₂ 2× and thereaction mixture was stirred at room temperature for 18 hrs. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure to give Example 128 as a colorless oil. Yield (0.0454g, 74%); ¹H NMR (400 MHz, CD₃OD) δ 7.20-7.25 (m, 2H), 7.13-7.17 (m, 1H),7.09-7.12 (m, 1H), 4.45 (d, J=6.3 Hz, 1H), 3.64 (q, J=6.1 Hz, 1H),2.64-2.69 (m, 2H), 2.52 (d, J=5.9 Hz, 2H), 1.40-1.73 (m, 12H), 1.26-1.38(m, 2H); RP-HPLC (Method 2) t_(R)=5.13 min, 92.2% (AUC); ESI MSm/z=294.46 [M+H]⁺.

Example 129 Preparation of(1R,2R)-3-amino-1-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diol

(1R,2R)-3-Amino-1-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diolwas prepared following the method used in Example 128.

Step 1. Dihydroxylation of ally azide 114 was conducted using AD-mix-ato give (1R,2R)-3-azido-1-(3-bromophenyl)propane-1,2-diol. Yield (0.966g, 96%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (t, J=1.6 Hz, 1H), 7.40 (ddd,J=1.2, 2.0, 7.6 Hz, 1H), 7.29-7.33 (m, 1H), 7.25 (t, J=7.6 Hz, 1H), 5.52(d, J=5.1 Hz, 1H), 5.26 (d, J=5.9 Hz, 1H), 4.51 (t, J=4.7 Hz, 1H), 3.15(dd, J=3.3, 12.5 Hz, 1H), 3.02 (dd, J=8.0, 12.7 Hz, 1H).

Step 2. Reduction and protection of(1R,2R)-3-azido-1-(3-bromophenyl)propane-1,2-diol gaveN-((2R,3R)-3-(3-bromophenyl)-2,3-dihydroxypropyl)-2,2,2-trifluoroacetamideas a white solid. Yield 0.66 g, 69%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.21(t, J=5.3 Hz, 1H), 7.52 (t, J=1.6 Hz, 1H), 7.40 (ddd, J=1.2, 2.0, 7.8Hz, 1H), 7.30-7.33 (m, 1H), 7.25 (t, J=7.6 Hz, 1H), 5.48 (d, J=5.1 Hz,1H), 5.00 (d, J=5.9 Hz, 1H), 4.51 (t, J=4.7 Hz, 1H), 3.70-3.76 (m, 1H),3.24 (dt, J=4.9, 13.3 Hz, 1H), 2.98 (ddd, J=5.7, 8.8, 13.3 Hz, 1H).

Step 3. Coupling ofN-((2R,3R)-3-(3-bromophenyl)-2,3-dihydroxypropyl)-2,2,2-trifluoroacetamidewith olefin 117 gaveN-((2R,3R)-2,3-dihydroxy-3-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propyl)-2,2,2-trifluoroacetamideas a brownish foam. Yield (0.1958 g, 82%). ¹H NMR (400 MHz, DMSO-d₆) δ9.19 (t, J=5.3 Hz, 1H), 7.35-7.37 (m, 1H), 7.20-7.26 (m, 2H), 7.13-7.18(m, 1H), 6.51 (d, J=16.2 Hz, 1H), 6.33 (d, J=16.0 Hz, 1H), 5.33 (d,J=4.9 Hz, 1H), 4.94 (d, J=5.7 Hz, 1H), 4.46 (t, J=4.8 Hz, 1H), 4.41 (s,1H), 3.70-3.76 (m, 1H), 3.18 (dt, J=4.5, 13.3 Hz, 1H), 2.99 (ddd, J=6.1,8.8, 14.3 Hz, 1H), 1.54-1.66 (m, 2H), 1.36-1.54 (m, 7H), 1.18-1.26 (m,1H).

Step 4. Deprotection ofN-((2R,3R)-2,3-dihydroxy-3-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propyl)-2,2,2-trifluoroacetamidegave(1R,2R)-3-amino-1-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propane-1,2-diolas a colorless oil. Yield (0.16 g, quant.). ¹H NMR (400 MHz, MeOH-d₄) δ7.42-7.44 (m, 1H), 7.30 (dt, J=1.6, 7.6 Hz, 1H), 7.27 (t, J=7.4 Hz, 1H),7.21 (dt, J=1.6, 7.2 Hz, 1H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (d, J=16.0Hz, 1H), 4.50 (d, J=5.9 Hz, 1H), 3.62-2.70 (m, 1H), 2.51-2.58 (m, 2H),1.66-1.77 (m, 2H), 1.48-1.66 (m, 7H), 1.28-1.40 (m, 1H). ¹³C NMR (100MHz, MeOH-d₄) δ 142.3, 137.9, 137.7, 128.3, 126.7, 125.7, 125.6, 124.6,76.0, 75.8, 71.2, 43.6, 37.5, 25.5, 21.9, 20.9. ESI MS m/z 292.3 [M+H]+;HPLC (Method 1) 96% (AUC), t_(R)=4.73 min.

Step 5. Hydrogenation of(1R,2R)-3-amino-1-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propane-1,2-diolgave Example 129 as a colorless oil. Yield (0.0380 g, 77%); ¹H NMR (400MHz, CD₃OD) δ 7.20-7.25 (m, 2H), 7.13-7.17 (m, 1H), 7.09-7.12 (m, 1H),4.45 (d, J=6.3 Hz, 1H), 3.64 (q, J=6.1 Hz, 1H), 2.64-2.69 (m, 2H), 2.52(d, J=5.9 Hz, 2H), 1.40-1.73 (m, 12H), 1.26-1.38 (m, 2H); RP-HPLC(Method 2) t_(R)=5.17 min, 94.4% (AUC); ESI MS m/z=294.46 [M+H]⁺.

Example 130 Preparation of(1S,2R)-3-amino-1-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diol

(1S,2R)-3-Amino-1-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diolwas prepared following the method shown in Scheme 24.

Step 1: A fresh solution of vinyl magnesium bromide (30.0 mL of a 1.0 Msolution in THF, 30 mmol) was slowly added under argon to an ice-coldsolution of 3-bromobenzaldehyde (30) (3.2 mL, 27.3 mmol) in anhydrousdiethyl ether (50 mL). The reaction mixture was stirred at 0° C. for 20min, after which aqueous solution of NH₄Cl (25%, 50 mL) was added. Themixture was allowed to warm to room temperature, layers were separatedand aqueous layer was extracted with hexane. Combined organic layerswere washed with brine, concentrated under reduced pressure and purifiedby flash column chromatography (silica gel, 5% to 300% EtOAc/hexanesgradient) to give allyl alcohol 120 as a colorless oil. Yield (4.22 g,73%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.47-7.49 (m, 1H), 7.40 (dt, J=1.8,7.4 Hz, 1H), 7.24-7.32 (m, 2H), 5.85-5.94 (m, 1H), 5.61 (d, J=4.5 Hz,1H), 5.24 (dt, J=1.8, 17.0 Hz, 1H), 5.00-5.07 (m, 2H).

Step 2. To a cold (−23° C.) mixture of powdered 4A molecular sieves (6.4g) and titanium tetraisopropoxide (5.5 mL, 18.8 mmol) in anhydrousCH₂Cl₂ (110 mL) was added L-(+)-diisopropyl tartrate (DIPT, 4.7 mL,22.49 mmol) under inert atmosphere. The reaction mixture was stirred at−20° C. and a solution of allyl alcohol 120 (4.0 g, 18.8 mmol) inanhydrous CH₂Cl₂ (80 mL) was added over 5 mins. After the reactionmixture was stirred at −20° C. for 30 min, tert-butyl hydroperoxidesolution (5.0-6.0 M in nonane, 2 mL, ca 10.0 mmol) was added. Thereaction mixture was stirred at −20° C. for 7.5 nrs, kept at −20° C.overnight, stirred at −20° C. for another 7 hrs and left at −20° C. andthen kept at −20° C. for 43 hrs. An aqueous solution of L-tartaric acid(10%, 110 mL) was added to the reaction mixture, the mixture was stirredfor 10 min at room temperature, then saturated aqueous solution ofNa₂SO₄ (20 mL) was added. The mixture was stirred vigorously for 1 h atroom temperature, layers were separated. Aqueous layer was extractedwith diethyl ether, then with EtOAc. Combined organic layers were washedwith brine, dried over anhydrous NaSO₄, filtered and the filtrateconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (silica gel, 30% to 70% EtOAc/hexanes gradient) togive a mixture of epoxide 121, DIPT (1:1 molar ratio) and unreacted 120as a colorless oil. Re-purified by flash column chromatography (silicagel, 5% to 10% EtOAc/CH₂Cl₂ gradient) gave a mixture of epoxide 121 andDIPT (1:0.85 molar ratio) as a colorless oil, which was used in the nextstep without additional purification. Yield (3.44 g, 85.6%); ¹H NMR (400MHz, DMSO-d₆) δ 7.54 (t, J=1.6 Hz, 1H), 7.45 (ddd, J=1.2, 2.0, 7.8 Hz,1H), 7.34-7.38 (m, 1H), 7.29 (t, J=7.6 Hz, 1H), 5.68 (d, J=4.5 Hz, 1H),4.41 (t, J=4.7 Hz, 1H), 2.99-3.03 (m, 1H), 2.69 (ABd, J=5.5, 3.9 Hz,1H), 2.63 (ABd, J=5.3, 2.7 Hz, 1H).

Step 3. A solution of the crude epoxide 121 (0.47 g, 0.803 mmol),ammonium hydroxide (25%, 5 mL) and NH₃/MeOH (7N, 5 mL) was stirred in apressure bottle at room temperature for 20 hrs, and then concentratedunder reduced pressure. The residue was dissolved in MTBE:MeOH (1:1, 10mL) and ethyl trifluoroacetate (3.0 mL) was added. The mixture wasstirred at room temperature for lh, concentrated under reduced pressureand the residue was purified by flash column chromatography (silica gel,30% to 60% EtOAc/hexanes gradient) to give trifluoroacetamide 122 as acolorless oil. Yield (0.248 g, 66%); ¹H NMR (400 MHz, DMSO-d₆) δ 9.17(br. t, 1H), 7.51 (t, J=1.8 Hz, 1H), 7.40 (ddd, J=1.2, 2.0, 7.9 Hz, 1H),7.30-7.33 (m, 1H), 7.25 (t, J=7.8 Hz, 1H), 5.57 (d, J=4.7 Hz, 1H), 4.96(d, J=6.06 Hz, 1H), 4.39 (t, J=5.5 Hz, 1H), 3.62-3.69 (m, 1H), 3.38 (dt,J=4.1, 13.7 Hz, 1H), 3.05-3.13 (m, 1H).

Step 4. Coupling of bromide 122 with olefin 117 following the methodused in Example 128 except that anhydrous degassed DMF (1 mL) was usedas the reaction solvent, the reaction was heated at 90° C. for 3 hrsthen at 60° C. overnight. After addition of water, the product wasextracted with EtOAc (3×) to give olefin 123 as a colorless oil. Yield(0.194 g, 70%); ¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (t, J=5.7 Hz, 1H),7.35-7.39 (m, 1H), 7.19-7.25 (m, 2H), 7.13-7.18 (m, 1H), 6.51 (d, J=16.0Hz, 1H), 6.34 (d, J=16.0 Hz, 1H), 5.41 (d, J=4.5 Hz, 1H), 4.86 (d, J=6.3Hz, 1H), 4.39-4.43 (m, 2H), 3.66-3.73 (m, 1H), 3.37 (ddd, J=3.3, 4.7,13.3 Hz, 1H), 3.08-3.16 (m, 1H), 1.55-1.67 (m, 2H), 1.37-1.54 (m, 7H),1.18-1.25 (m, 1H).

Step 5. A mixture of trifluoroacetamide 123 (0.189 g, 0.488 mmol),NH₃/MeOH (7N, 3.0 mL) and ammonium hydroxide (10.0 mL) was stirred atroom temperature for 68 hrs and concentrated under reduced pressure. Theresidue was purified by flash chromatography using a gradient of 50% to100% 7N NH₃/MeOH in EtOAc/hexanes to give crude amine as a colorlessoil. The amine was re-purified by flash chromatography using 20% 7NNH₃/MeOH in CH₂Cl₂ to give alkene 124 as a colorless oil. Yield (0.065g, 46%); ¹H NMR (400 MHz, MeOH-d₄) δ 7.42-7.45 (m, 1H), 7.22-7.32 (m,3H), 6.61 (d, J=16.2 Hz, 1H), 6.36 (d, J=16.0 Hz, 1H), 4.58 (d, J=6.1Hz, 1H), 3.71-3.76 (m, 1H), 2.92 (dd, J=3.5, 13.1 Hz, 1H), 2.77 (dd,J=8.0, 13.1 Hz, 1H), 1.47-1.76 (m, 9H), 1.25-1.40 (m, 1H); ¹³C NMR (100MHz, MeOH-d₄) δ 142.7, 137.8, 137.5, 128.1, 126.9, 125.8, 125.4, 124.8,76.1, 75.7, 71.2, 43.3, 37.5, 25.5, 21.9; RP-HPLC (Method 2) 97% (AUC),t_(R)=5.44 min; ESI MS m/z 292.5 [M+H]⁺.

Step 6. Hydrogenation of alkene 124 following the method used in Example128 gave Example 130 as a colorless oil. Yield (0.0513 g, quant); ¹H NMR(400 MHz, CD₃OD) δ 7.19-7.25 (m, 2H), 7.15-7.19 (m, 1H), 7.07-7.11 (m,1H), 4.52 (d, J=6.3 Hz, 1H), 3.65 (ddd, J=3.3, 6.1, 9.6 Hz, 1H), 2.82(dd, J=3.5, 13.1 Hz, 1H), 2.63-2.70 (m, 3H), 1.42-1.74 (m, 12H),1.26-1.37 (m, 2H); ¹³C NMR (100 MHz, MeOH-d₄) δ 143.1, 142.3, 128.0,127.3, 126.8, 124.1, 76.2, 75.5, 70.9, 44.5, 43.2, 37.0, 29.4, 25.9,22.1, 17.2; RP-HPLC (Method 2) t_(R)=5.30 min, 92.7% (AUC); ESI MSm/z=294.46 [M+H]⁺

Example 131 Preparation of(1R,2S)-3-amino-1-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diol

(1R,2S)-3-Amino-1-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)propane-1,2-diolwas prepared following the method used in Example 130.

Step 1. Epoxidation of allyl alcohol 120 using D-(−)-diisopropyltartrate gave crude (R)-(3-bromophenyl)((S)-oxiran-2-yl)methanol as acolorless oil. Yield (4.12 g, quant.); ¹H NMR (400 MHz, DMSO-d₆) δ 7.54(t, J=1.6 Hz, 1H), 7.45 (ddd, J=1.2, 2.0, 7.8 Hz, 1H), 7.34-7.38 (m,1H), 7.29 (t, J=7.6 Hz, 1H), 5.68 (d, J=4.5 Hz, 1H), 4.41 (t, J=4.7 Hz,1H), 2.99-3.03 (m, 1H), 2.69 (ABd, J=5.5, 3.9 Hz, 1H), 2.63 (ABd, J=5.3,2.7 Hz, 1H).

Step 3. Epoxide ring opening and protection of amine withtrifluoroacetyl group gaveN-((2S,3R)-3-(3-bromophenyl)-2,3-dihydroxypropyl)-2,2,2-trifluoroacetamideas a colorless oil. Yield (0.322 g, 42%); ¹H NMR (400 MHz, DMSO-d₆) δ9.14 (t, J=5.7 Hz, 1H), 7.35-7.39 (m, 1H), 7.19-7.25 (m, 2H), 7.13-7.18(m, 1H), 6.51 (d, J⁼16.0 Hz, 1H), 6.34 (d, J=16.0 Hz, 1H), 5.41 (d,J=4.5 Hz, 1H), 4.86 (d, J=6.3 Hz, 1H), 4.39-4.43 (m, 2H), 3.66-3.73 (m,1H), 3.37 (ddd, J=3.3, 4.7, 13.3 Hz, 1H), 3.08-3.16 (m, 1H), 1.55-1.67(m, 2H), 1.37-1.54 (m, 7H), 1.18-1.25 (m, 1H).

Step 4. Heck coupling ofN-((2S,3R)-3-(3-bromophenyl)-2,3-dihydroxypropyl)-2,2,2-trifluoroacetamidewith olefin 105 gaveN-((2S,3R)-2,3-dihydroxy-3-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propyl)-2,2,2-trifluoroacetamideas a colorless oil. Yield (0.266 g, 76%); ¹H NMR (400 MHz, DMSO-d₆) δ9.14 (t, J=5.7 Hz, 1H), 7.35-7.39 (m, 1H), 7.19-7.25 (m, 2H), 7.13-7.18(m, 1H), 6.51 (d, J=16.0 Hz, 1H), 6.34 (d, J=16.0 Hz, 1H), 5.41 (d,J=4.5 Hz, 1H), 4.86 (d, J=6.3 Hz, 1H), 4.39-4.43 (m, 2H), 3.66-3.73 (m,1H), 3.37 (ddd, J=3.3, 4.7, 13.3 Hz, 1H), 3.08-3.16 (m, 1H), 1.55-1.67(m, 2H), 1.37-1.54 (m, 7H), 1.18-1.25 (m, 1H).

Step 5. Deprotection ofN-((2S,3R)-2,3-dihydroxy-3-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propyl)-2,2,2-trifluoroacetamidegave(1R,2S)-3-amino-1-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propane-1,2-diolas a colorless oil. Yield (0.104 g, 52%); ¹H NMR (400 MHz, MeOH-d₄) δ7.42-7.45 (m, 1H), 7.22-7.32 (m, 3H), 6.61 (d, J=16.2 Hz, 1H), 6.36 (d,J=16.0 Hz, 1H), 4.58 (d, J=6.1 Hz, 1H), 3.71-3.76 (m, 1H), 2.92 (dd,J=3.5, 13.1 Hz, 1H), 2.77 (dd, J=8.0, 13.1 Hz, 1H), 1.47-1.76 (m, 9H),1.25-1.40 (m, 1H).

Step 6. Hydrogenation of(1R,2S)-3-amino-1-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propane-1,2-diolgave Example 131 as a colorless oil. Yield (0.0834 g, 96%); ¹H NMR (400MHz, CD₃OD) δ 7.19-7.25 (m, 2H), 7.15-7.19 (m, 1H), 7.07-7.11 (m, 1H),4.52 (d, J=6.3 Hz, 1H), 3.65 (ddd, J=3.3, 6.1, 9.6 Hz, 1H), 2.82 (dd,J=3.5, 13.1 Hz, 1H), 2.63-2.70 (m, 3H), 1.42-1.74 (m, 12H), 1.26-1.37(m, 2H); RP-HPLC (Method 2) t_(R)=5.31 min, 88.0% (AUC); ESI MSm/z=294.48 [M+H]⁺

Example 132 Preparation of(R)-3-(3-(3-aminopropyl)phenyl)-1-phenylpropan-1-ol

(R)-3-(3-(3-Aminopropyl)phenyl)-1-phenylpropan-1-ol was preparedfollowing the method used in Example 2.

Step 1: Sonogashira coupling of (R)-1-phenylprop-2-yn-1-ol withN-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide gave(S)-2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-phenylprop-1-ynyl)phenyl)propyl)acetamideas an amber oil. Yield (0.73 g, 62%): ¹H NMR (400 MHz, DMSO-d₆) δ7.57-7.59 (m, 2H), 7.17-7.40 (m, 7H), 5.60 (s, 1H), 3.26-3.29 (m, 2H),2.62 (t, J=7.6 Hz, 2H), 1.86 (quint, J=6.8 Hz, 2H)

Step 2: Deprotection of(S)-2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-phenylprop-1-ynyl)phenyl)propyl)acetamidegave (S)-3-(3-(3-Aminopropyl)phenyl)-1-phenylprop-2-yn-1-ol as a paleyellow oil. Yield (0.239 g, 30%): ¹H NMR (400 MHz, CD₃OD) δ 7.56-7.59(m, 1H), 7.16-7.39 (m, 8H), 5.60 (s, 1H), 2.58-2.62 (m, 4H), 1.69-1.77(m, 2H).

Step 3: Reduction of(S)-3-(3-(3-Aminopropyl)phenyl)-1-phenylprop-2-yn-1-ol following themethod used in Example 2, followed by flash chromatography (10-100% (7NNH₃/MeOH)/DCM gradient), gave Example 132 as a colorless oil. Yield(0.103 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.36 (m, 4H), 7.24-7.30(m, 1H), 7.15-7.21 (m, 1H), 6.97-7.03 (m, 3H), 4.66 (dd, J=5.2, 8.0 Hz,1H), 2.56-2.76 (m, 6H), 1.96-2.16 (m, 2H), 1.69-1.79 (m, 2H), 1.50-1.70(brs, 3H). ESI MS m/z 270.21 [m+H]+, 252.17 [m+H−OH]⁺.

Example 133 Preparation of3-(3-(2-cycloheptylethyl)phenyl)propan-1-amine

3-(3-(2-cycloheptylethyl)phenyl)propan-1-amine was prepared followingthe method shown in Scheme 25.

Step 1: LAH (180 mL of a 1M solution, 176 mmol) was added slowly to asolution of acid 125 (25 g, 176 mmol), in anhydrous THF (500 mL) underargon at 5° C. The reaction was allowed to warm to room temperature,stirred 1 h, cooled again to 5° C., then quenched by slow addition ofsaturated aqueous Na₂SO₄. The resultant precipitate was removed byfiltration, then the filtrate was extracted with EtOAc, washed withwater and brine, dried over Na₂SO₄, filtered and concentrated to givethe alcohol 126 as a colorless oil. Yield (21 g, 98%). ¹H NMR (400 MHz,CDCl₃) δ 3.38 (d, J=6.4 Hz, 2H), 1.38-1.80 (m, 12H), 1.10-1.20 (m, 2H).

Step 2: A solution of alcohol 126 (4.5 g, 35 mmol) in dichloromethane(10 mL) was added to a stirring mixture of pyridinium chlorochromate(9.4 g, 43.8 mmol) and celite (10 g) in dichloromethane (100 mL) and thereaction stirred 16 hr. The mixture was filtered through a pad of silicagel and the pad rinsed with diethyl ether. The combined filtrate wasconcentrated, giving impure aldehyde 127 as a green oil, which was takenon to the next step without purification. Yield (4.1 g, 93%). ¹H NMR(400 MHz, CDCl₃) δ 9.58 (d, J=0.8 Hz, 1H), 2.28-2.36 (m, 1H), 1.88-1.95(m, 2H), 1.40-1.70 (m, 10H).

Step 3: Sodium trichloroacetate was added in 3 aliquots over 10 min to astirred solution of aldehyde 127 (14.9 g, 118 mmole) and trichloroaceticacid (19.3 g, 177 mmol) in DMF (150 mL). The reaction was stirred atroom temperature for 2 h, cooled in an ice bath, then quenched anddiluted with water. The solution was extracted with hexanes and washedwith saturated aqueous NH₄Cl, water, and brine. The combined organicswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure, giving impure alcohol 128 as a yellow oil, which was taken onto the next step without purification. Yield (23.4 g, 80%). ¹H NMR (400MHz, CDCl₃) δ 3.95 (d, J=2.0 Hz, 1H), 2.85 (br s, 1H), 2.20-2.30 (m,1H), 1.88-2.08 (m, 1H), 1.36-1.84 (m, 11H).

Step 4: p-toluenesulfonyl chloride (3.34 g, 17.5 mmol) was added to asolution of alcohol 128 (4.3 g, 17.5 mmol), triethylamine (3.6 mL, 26.3mmol), and diazabicyclooctane (0.586 g, 5.2 mmol) in 40 mLdichloromethane and stirred at room temperature for 90 min. The reactionwas washed with water (40 mL), and 5N HCl (40 mL). The combined aqueouswas extracted with dichloromethane (40 mL) and the combined organicsfurther washed with 2N HCl, water, and brine, then dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification by flashchromatography (0-10% EtOAc/hexanes gradient) gave the sulfonate 129 aspale yellow crystals. Yield (2.65 g, 38%): ¹H NMR (400 MHz, CDCl₃) δ7.81 (d, J=8.8 Hz, 2H), 7.32 (d, J=8 Hz, 2H), 2.43 (s, 3H), 2.24-2.32(m, 1H), 1.98-2.06 (s, 1H), 1.78-1.88 (m, 1H), 1.60-1.73 (m, 3H),1.28-1.60 (m, 8H).

Step 5: Methyllithium (7.0 mL of a 1.6 M solution in diethyl ether,11.25 mmol) was added dropwise to a stirring solution of sulfonate 129(1 g, 2.5 mmol) in anhydrous THF (15 mL) under argon at 5° C. Thereaction was allowed to warm to room temperature, stirred 16 hr, thenquenched by the slow addition of saturated aqueous NH₄Cl. The mixturewas extracted with hexanes, and the combined organics washed with brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure,giving the ethynylcycloheptane (130) as a yellow oil. Yield (0.270 g,88%)¹H NMR (400 MHz, CDCl₃) δ 2.51 (s, 1H), 1.99 (d, J=2.8 Hz, 1H),1.73-1.83 (m, 2H), 1.55-1.70 (m, 4H), 1.35-1.55 (m, 6H).

Step 6: Sonogashira coupling of ethynylcycloheptane (130) withN-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide following themethod used in Example 2, followed by flash chromatography (0-25%EtOAc/hexanes gradient), gave alkyne 131 as an amber oil. Yield (0.556g, 59%): ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.26 (m, 3H), 7.03-7.08 (m, 1H),6.28 (br s, 1H), 3.36 (dt, J=6.8, 6.8 Hz, 2H), 2.75-2.83 (m, 1H), 2.63(t, J=7.2 Hz, 2H), 1.85-1.95 (m, 4H), 1.69-1.80 (m, 4H), 1.48-1.65 (m,6H).

Step 7: Deprotection of alkyne 131 following the method used in Example2, followed by flash chromatography (5% (7N NH3/MeOH)/dichloromethane),gave alkyne 132 as a colorless oil. Yield (0.226 g, 56%): ¹H NMR (400MHz, CDCl₃) δ 7.13-7.25 (m, 3H), 7.03-7.08 (m, 1H), 2.74-2.82 (m, 1H),2.69 (t, J=7.2 Hz, 2H), 2.59 (t, J=7.2 Hz, 2H), 1.84-1.94 (m, 2H),1.68-1.80 (m, 6H), 1.46-1.64 (m, 6H), 1.30 (br s, 2H).

Step 8: Reduction of alkyne 132 following the method used in Example 2,followed by flash chromatography (10-100% (7N NH₃/MeOH)/DCM gradient),gave Example 133 as a colorless oil. Yield (0.081 g, 80%): ¹H NMR (400MHz, CD3OD) δ 7.13 (t, J=7.2 Hz, 1H), 6.92-7.00 (m, 3H), 2.52-2.65 (m,6H), 1.70-1.80 (m, 4H), 1.60-1.70 (m, 2H), 1.36-1.60 (m, 9H), 1.18-1.28(m, 2H). ESI MS m/z 260.25 [m+H]⁺.

Example 134 Preparation of 4-(3-(2-aminoethylthio)phenethyl)heptan-4-ol

4-(3-(2-Aminoethylthio)phenethyl)heptan-4-ol was prepared following themethod shown in Scheme 26.

Step 1: 3-bromobenzenethiol (133) (3 g, 15.9 mmol), 2-bromoethanol (2.4g, 19.1 mmol), and K₂CO₃ (4.4 g, 32 mmol) were combined in acetone (20mL) and stirred at room temperature for 1 h. The acetone was removedunder reduced pressure and the residue extracted from water with ethylacetate. The ethyl acetate solution was washed with brine, dried withMgSO₄, filtered, and concentrated under reduced pressure, giving thealcohol 134 as a yellow oil without purification. Yield (3.6 g, 97%): ¹HNMR (400 MHz, CDCl₃) δ 7.49 (t, J=2.0 Hz, 1H), 7.31 (ddd, J=0.8, 1.6,8.0 Hz, 1H), 7.27 (ddd, J=0.8, 1.6, 8.0 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H),3.75 (t, J=6.4 Hz, 2H), 3.10 (t, J=6.4 Hz, 2H), 2.18 (brs, 1H).

Step 2: Mitsunobu coupling of 134 with phthalimide following the methodused in Example 21, followed by flash chromatography (5-20% ethylacetate/hexanes gradient) gave the bromide 135 as a white solid. Yield(4.04 g, 72%): ¹H NMR (400 MHz, CDCl₃) δ 7.77-7.84 (m, 2H), 7.66-7.72(m, 2H), 7.50 (t, J=2.0 Hz, 1H), 7.30 (ddd, J=0.8, 1.6, 7.6 Hz, 1H),7.19 (ddd, J=0.8, 1.6, 7.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 3.93 (t,J=7.2 Hz, 2H), 3.22 (J=7.2 Hz, 2H).

Step 3: Deprotection of the bromide 135 following the method used inExample 9 gave the amine 136 as a yellow oil. Yield (1.56 g, 98%): ¹HNMR (400 MHz, CDCl₃) δ 7.44 (t, J=2.0 Hz, 1H), 7.26 (ddd, J=0.8, 1.6,7.6 Hz, 1H), 7.21 (ddd, J=0.8, 1.6, 7.6 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H),2.87-3.0 (m, 2H), 2.82-2.86 (m, 2H), 1.7-2.4 (brs, 2H).

Step 4: Amidation of the amine 136 according to the method used inExample 2, followed by flash chromatography (5-20% ethyl acetate/hexanesgradient) gave the trifluoroamide 137 as a colorless oil. Yield (1.75 g,80%): ¹H NMR (400 MHz, CDCl₃) δ 7.50 (t, J=2.0 Hz, 1H), 7.35 (ddd,J=0.8, 1.6, 7.6 Hz, 1H), 7.29 (ddd, J=0.8, 1.6, 7.6 Hz, 1H), 7.16 (t,J=8.0 Hz, 1H), 6.81 (brs, 1H), 3.55 (app q, J=6.4 Hz, 2H), 3.10 (t,J=6.4 Hz, 2H).

Step 5: Sonogashira coupling of 4-ethynylheptan-4-ol with theN-(2-(3-bromophenylthio)ethyl)-2,2,2-trifluoroacetamide (137) followingthe method used in Example 2, followed by flash chromatography (5-50%ethyl acetate/hexanes gradient) gave alkynol 138 as a colored solid.Yield (0.22 g, 52%): ¹H NMR (400 MHz, DMSO) δ 9.52-9.60 (m, 1H),7.26-7.36 (m, 3H), 7.16-7.20 (m, 1H), 5.11 (s, 1H), 3.60 (ddd, J=6.4 Hz,2H), 3.11 (t, J=7.2 Hz, 2H), 1.52-1.62 (m, 4H), 1.38-1.52 (m, 4H), 0.89(t, J=7.2 Hz, 6H).

Step 6: Deprotection of alkynol 138 following the method used in Example2, followed by flash chromatography (0-10% (7N NH₃/MeOH)/dichloromethanegradient) gave amine 139 as a yellow oil. Yield (0.89 g, 68%): ¹H NMR(400 MHz, MeOD) δ 7.36-7.38 (m, 1H), 7.32 (dt, J=1.6, 7.6 Hz, 1H), 7.25(t, J=7.6 Hz, 1H), 7.20 (dt, J=1.6, 7.6 Hz, 1H), 3.01 (t, J=6.4 Hz, 2H),2.78 (brs, 2H), 1.62-1.74 (m, 4H), 1.50-1.62 (m, 4H), 0.97 (t, J=7.2 Hz,6H).

Step 7: Reduction of amine 139 following the method used in Example 1,followed by flash chromatography (10-100% (7N NH₃/MeOH)/DCM gradient),gave Example 134 as a colorless oil. Yield (0.042 g, 75%): ¹H NMR (400MHz, CDCl₃) δ7.16-7.21 (m, 3H), 6.99-7.03 (m, 1H), 2.99 (t, J=5.6 Hz,2H), 2.91 (brs, 2H), 2.56-2.62 (m, 2H), 1.66-1.73 (m, 2H), 1.40-1.60 (m,7H), 1.28-1.40 (m, 4H), 0.924 (t, J=7.2 Hz, 6H). ESI MS m/z 296.29[m+H]⁺, 278.25 [m+H−OH]⁺.

Example 135 Preparation of4-(3-(2-aminoethylsulfonyl)phenethyl)heptan-4-ol

4-(3-(2-Aminoethylsulfonyl)phenethyl)heptan-4-ol was prepared followingthe method shown in Scheme 27.

Step 1: To a solution of the bromide 137 (0.6 g, 1.83 mmol) in ethanol(10 mL) at room temperature was added ammonium molybdate tetrahydrate(0.68 g, 0.55 mmol (30%)), and hydrogen peroxide (1.9 mL of a 30% aqsolution, 18.3 mmol). The reaction was stirred overnight then quenchedwith saturated aqueous Na₂S₂O₃ (4 mL). Ethanol was removed in-vacuo andthe residue was extracted from water with ethyl acetate. The combinedorganics was washed with brine, dried over MgSO₄, filtered, concentratedin-vacuo, and purified by flash chromatography (5-50% ethylacetate/hexanes gradient), giving the sulfone 139 as a white waxy solid.Yield (0.615 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ 8.05 (t, J=2.0 Hz, 1H),7.81-7.87 (m, 2H), 7.49 (t, J=8.0 Hz, 1H), 7.25 (brs, 1H), 3.81-3.88 (m,2H), 3.33-3.38 (m, 2H).

Step 2: Sonogashira coupling of 139 with 4-ethynylheptan-4-ol followingthe method used in Example 2, followed by flash chromatography (5-50%ethyl acetate/hexanes gradient) gave alkynol 140 as a yellow oil. Yield(0.515 g, 72%): ¹H NMR (400 MHz, DMSO) δ 7.93 (m, 1H), 7.80-7.84 (m,1H), 7.69-7.73 (m, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.27 (brs, 1H),3.79-3.86 (m, 2H), 3.31-3.36 (m, 2H), 1.93 (brs, 1H), 1.64-1.78 (m, 4H),1.51-1.64 (m, 4H), 0.98 (t, J=7.2 Hz, 6H).

Step 3: Deprotection of trifluoroamide 140 according to the method usedin Example 2, followed by flash chromatography (0-10% (7NNH₃/MeOH)/dichloromethane gradient), gave alkyne 141 as a yellow oil.Yield (0.21 g, 52%): ¹H NMR (400 MHz, MeOD) δ 7.90-7.92 (m, 1H),7.78-7.82 (m, 1H), 7.62-7.64 (m, 1H), 7.48 (t, J=8.0 Hz, 1H), 3.20-3.25(m, 2H), 3.07-3.15 (m, 2H), 1.81 (brs, 3H), 1.62-1.75 (m, 4H), 1.50-1.62(m, 4H), 0.96 (t, J=7.2 Hz, 6H).

Step 4: Reduction of the alkyne 141 following the method used in Example2, followed by flash chromatography (10-100% (7N NH₃/MeOH)/DCMgradient), gave Example 135 as a colorless oil. Yield (0.081 g, 80%): ¹HNMR (400 MHz, CDCl₃) δ 7.69-7.74 (m, 2H), 7.44-7.49 (m, 2H), 3.20-3.24(m, 2H), 3.08-3.13 (m, 2H), 2.69-2.75 (m, 2H), 1.68-1.74 (m, 2H),1.43-1.52 (m, 7H), 1.26-1.40 (m, 4H), 0.92 (t, 8.0 Hz, 6H). ESI MS m/z328.31 [m+H]+, 310.27 [m+H−OH]⁺.

Example 136 Preparation of 4-(3-(2-aminoethylamino)phenethyl)heptan-4-ol

4-(3-(2-Aminoethylamino)phenethyl)heptan-4-ol was prepared following themethod shown in Scheme 28.

Step 1: To a stirred solution of2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (142, 3.0 g, 15.9 mmol) inCH₂Cl₂ (1000 ml) was added 3-bromoaniline (143, 2.2 g, 13.0 mmol),sodium triacetoxyborohydride (4.2 g, 20 mmol) and acetic acid (1.2 g, 20mmol). The reaction was stirred at room temperature overnight, thenwashed with saturated ammonium chloride, water, and brine. The combinedorganics were dried over MgSO₄, filtered, and concentrated in-vacuo.Purification by flash chromatography (10-40% ethyl acetate/hexanesgradient) gave benzyl bromide 144 as a yellow oil. Yield (1.7 g, 38%).¹H NMR (400 MHz, CDCl₃) δ 7.80-7.88 (m, 2H), 7.68-7.78 (m, 2H),6.93-6.99 (m, 1H), 6.72-6.77 (m, 2H), 6.49-6.54 (m, 1H), 4.23 (brs, 1H),3.95 (t, J=6.0 Hz, 2H), 3.39 (t, J=6.0 Hz, 2H).

Step 2: Deprotection of benzyl bromide 144 following the method used inExample 9, followed by flash chromatography (0-10% (7NNH₃/MeOH)/dichloromethane) gradient), gave diamine 145 as a yellow oil.Yield (0.286 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 6.99 (t, J=8.0 Hz, 1H),6.76-6.81 (m, 1H), 6.74 (t, J=2.0 Hz, 1H), 6.49-6.54 (m, 1H), 4.19 (brs,1H), 3.13 (t, J=6.0 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 1.20 (brs, 2H).

Step 3: Amidation of diamine 145 following the method used in Example 2gave trifluoroamide 146 as a yellow, waxy solid. Yield (0.462 g,quantitative). ¹H NMR (400 MHz, CDCl₃) δ 7.01 (t, J=8.0 Hz, 1H), 6.99(brs, 1H), 6.82-6.86 (m, 1H), 6.74 (t, J=2.4 Hz, 1H), 6.50-6.55 (m, 1H),4.03 (brs, 1H), 3.55 (q, J=6.0, Hz, 2H), 3.33 (t, J=6.0 Hz, 2H).

Step 4: Sonogashira coupling of 146 with 4-ethynylheptan-4-ol followingthe method used in Example 2, followed by flash chromatography (5-30%ethyl acetate/hexanes gradient), gave alkynol 147 as an orange oil.Yield (0.30 g, 60%). ¹H NMR (400 MHz, CDCl₃) δ 7.54 (brs, 1H), 7.07 (t,J=8.0 Hz, 1H), 6.75-6.78 (m, 1H), 6.61-6.64 (m, 1H), 6.52-6.56 (m, 1H),3.51 (q, J=5.6 Hz, 2H), 3.32 (t, J=6.0 Hz, 2H), 1.63-1.71 (m, 4H),1.50-1.63 (m, 4H), 0.95 (t, J=7.2 Hz, 6H).

Step 5: Deprotection of alkynol 147 following the method used in Example2 followed by flash chromatography (0-10% (7N NH₃/MeOH)/dichloromethane)gradient), gave amine 148 as a yellow, waxy solid. Yield (0.14 g, 63%).¹H NMR (400 MHz, DMSO) δ 6.97-7.03 (m, 1H), 6.46-6.54 (m, 3H), 5.66 (t,J=5.2 Hz, 1H), 5.07 (s, 1H), 2.94 (q, J=6.4 Hz, 2H), 2.66 (t, J=6.4 Hz,2H), 1.38-1.62 (m, 10H), 0.88 (t, J=7.8 Hz, 6H).

Step 6: Reduction of the amine 148 following the method used in Example2, followed by flash chromatography (10-100% (7N NH₃/MeOH)/DCMgradient), gave Example 136 as a colorless oil. Yield (0.047 g, 84%): ¹HNMR (400 MHz, CDCl₃) δ7.08 (t, J=7.6 Hz, 1H), 6.53-6.57 (m, 1H),6.44-6.49 (m, 2H), 3.18 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H),2.51-2.57 (m, 2H), 1.68-1.74 (m, 2H), 1.42-1.50 (m, 6H), 1.28-1.40 (m,6H), 0.93 (t, J=7.2 Hz, 6H). ESI MS m/z 279.3 [m+H]⁺, 261.26 [m+H−OH]⁺.

Example 137 Preparation of3-amino-1-(3-(2-cycloheptylethyl)phenyl)propan-1-ol

3-amino-1-(3-(2-cycloheptylethyl)phenyl)propan-1-ol was preparedfollowing the method used in Example 2.

Step 1: Sonogashira coupling ofN-(3-(3-bromophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (43) withethynylcycloheptane, followed by flash chromatography (5-40%EtOAc/hexanes gradient), gaveN-(3-(3-(cycloheptylethynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas an amber oil. Yield (0.507 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ 7.42(br s, 1H), 7.34-7.36 (m, 1H), 7.19-7.33 (m, 3H), 4.81 (q, J=4.0 Hz,1H), 3.48-3.68 (m, 1H), 3.32-3.42 (m, 1H), 2.74-2.82 (m, 1H), 2.48 (brs, 1H), 1.85-2.00 (m, 4H), 1.70-1.80 (m, 4H), 2.46-1.64 (m, 6H).

Step 2: Deprotection ofN-(3-(3-(cycloheptylethynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidefollowed by flash chromatography (5% (7N NH₃/MeOH)/dichloromethane) gave3-amino-1-(3-(2-cycloheptylethynyl)phenyl)propan-1-ol as a yellow oil.Yield (0.173 g, 46%): ¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 1H), 7.18-7.30(m, 3H), 4.91 (d, J=6.8 Hz, 1H), 3.00 (br s, 5H), 2.74-2.82 (m, 1H),1.80-1.94 (m, 3H), 1.68-1.80 (m, 5H), 1.44-1.64 (m, 6H).

Step 3: Reduction of3-amino-1-(3-(2-cycloheptylethynyl)phenyl)propan-1-ol following themethod used in Example 2, followed by flash chromatography (10-100% (7NNH₃/MeOH)/DCM gradient), gave Example 137 as a colorless oil. Yield(0.076 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.26 (m, 3H), 7.03-7.07(m, 1H), 4.88-4.94 (m, 1H), 3.03-3.10 (m, 1H), 2.88-2.98 (m, 1H), 2.77(brs, 3H), 2.55-2.63 (m, 2H), 1.80-1.90 (m, 1H), 1.68-1.80 (m, 3H),1.58-1.68 (m, 2H), 1.34-1.58 (m, 9H), 1.16-1.27 (m, 2H). ESI MS m/z276.29 [m+H]⁺, 258.25 [m+H−OH]⁺.

Example 138 Preparation of(R)-3-amino-1-(3-(4-Phenylbutyl)Phenyl)Propan-1-Ol

(R)-3-Amino-1-(3-(4-phenylbutyl)phenyl)propan-1-ol was preparedfollowing the method shown in Scheme 29.

Step 1: Chiral reduction of ketone 76 with (−)-Ipc₂BCl following themethod used in Example 70 after flash chromatography purification(gradient) gave (R)-alcohol 149 as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.50 (t, J=1.6 Hz, 1H), 7.43 (dt, J=7.2, 2.0 Hz, 1H), 7.21-7.27(m, 2H), 4.84 (dt, J=8.8, 3.2 Hz, 1H), 3.65-3.73 (m, 1H), 3.36-3.43 (m,1H), 2.47 (dd, J=2.9, 1.0 Hz, 1H), 1.80-2.00 (m, 2H).

Step 2. Sonogashira coupling between (R)-hydroxyaryl bromide 149 and4-phenylbutyne following the method used in Example 70 except that thereaction mixture was stirred at 70° C. for 4 h, and then at 60° C. for17 h, gave crude alkyne 150 as a light yellow oil which was used in thenext step without purification. Yield (0.49 g, 77%).

Step 3. Deprotection of 150 following the method used in Example 100(Determination of the Absolute Stereochemistry) gave amine 151 as acolorless oil. Yield (0.195 g, 60%); ¹H NMR (400 MHz, CD₃OD) δ 7.31-7.33(m, 1H), 7.15-7.29 (m, 8H), 4.67 (dd, J=8.0, 5.3 Hz, 1H), 2.87 (t, J=7.2Hz, 2H), 2.64-2.74 (m, 4H), 1.72-1.85 (m, 2H); ¹³C NMR (100 MHz, CD₃OD)δ 145.6, 140.9, 130.1, 128.8, 128.7, 128.4, 128.2, 126.1, 125.1, 124.1,89.0, 81.1, 72.0, 71.9, 41.5, 38.4, 35.0, 21.2; RP-HPLC, 96.4% (AUC);LC-MS m/z=280.2 [M+H]⁺.

Step 4. Hydrogenation of alkyne 151 was done following the method usedin Example 70 except that the reaction was run for 16 hrs. The reactionmixture was filtered and HCl/EtOH (7.4 M, 1 mL) was added to thefiltrate. The filtrate was concentrated under reduced pressure,dissolved in EtOAc and cooled to 0° C. The precipitate formed wascollected by filtration and dried in vacuo to give Example 138hydrochloride as a white solid. Yield (0.069 g, 75%); ¹H NMR (400 MHz,CD₃OD) δ 7.06-7.26 (m, 9H), 4.78 (dd, J=; 5.3, 7.4 Hz, 1H), 2.97-3.12(m, 2H), 2.58-2.66 (m, 2H), 1.92-2.01 (m, 2H), 1.58-1.67 (m, 2H); LC-MS(ESI+) 284.42 [M+H]⁺; RP-HPLC (Method 2): 97.6%, t_(R)=7.00 min.

Example 139 Preparation of(S)-4-(3-(2-amino-1-hydroxyethyl)phenethyl)heptan-4-ol

(S)-4-(3-(2-Amino-1-hydroxyethyl)phenethyl)heptan-4-ol was preparedfollowing the Scheme 30.

Step 1. Ketone 152 was reduced following the method used in Example 70to give hydroxybromide 153 as a colorless oil. Yield (0.818 g, 80%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.57 (t, J=1.8 Hz, 1H), 7.44 (ddd, J=1.0, 2.0,7.8 Hz, 1H), 7.35-7.39 (m, 1H), 7.28 (t, J=7.8 Hz, 1H), 5.90 (d, J=4.9Hz, 1H), 4.80 (dd, J=4.7, 6.5 Hz, 1H), 3.66 (ABd, J=4.5, 6.5 Hz, 1H),3.57 (ABd, J=4.5, 6.5 Hz, 1H).

Step 2. To a solution of bromide 153 (0.818 g, 2.92 mmol) in anhydrousTHF (10 mL) was added a solution of potassium tert-butoxide (1M, 3.5mL), the reaction mixture was stirred at room temperature for 15 min.concentrated under reduced pressure, and the residue was treated withwater. The product was extracted twice with EtOAc, organic layers werepooled, washed with brine, aq. NH₄Cl solution, dried over anhydrousMgSO₄, filtered and filtrate was concentrated under reduced pressure togive the (S)-2-(3-bromophenyl)oxirane (0.486 g) which was used in thenext step without purification.

(S)-2-(3-Bromophenyl)oxirane was dissolved in 7N NH₃/MeOH solution (5mL) and aqueous NH₄OH (25%, 5 mL) was added to the reaction mixturewhich was stirred at room temperature for 18 hrs. The reaction mixturewas concentrated under reduced pressure to give(S)-2-amino-1-(3-bromophenyl)ethanol (0.801 g) which was used in thenext step without purification.

(S)-2-Amino-1-(3-bromophenyl)ethanol was dissolved in anhydrous THF (5mL) and ethyl trifluoroacetate (1 mL) was added. The reaction mixturewas stirred at room temperature for 20 min, concentrated under reducedpressure and the residue was purified by flash chromatography to givetrifluoroacetamide 154 as a colorless oil. Yield (0.608 g, 67% for 3steps): ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (br. t, 1H), 7.46-7.49 (m, 1H),7.40-7.45 (m, 1H), 7.25-7.30 (m, 2H), 5.73 (d, J=4.7 Hz, 1H), 4.68 (dd,J=6.7, 11.3 Hz, 1H), 3.47-3.52 (m, 2H).

Step 3. Sonogashira coupling of bromide 154 with 4-ethynylheptan-4-olfollowing the method given in Example 70 except that P(o-tol)₃ was notused, gave alkynol 155 as a tan oil. Yield (0.59 g, 82%): ¹H NMR (400MHz, DMSO-d₆) δ 9.44 (br t, J=5.5 Hz, 1H), 7.22-7.32 (m, 4H), 5.65 (d,J=4.7 Hz, 1H), 4.67 (dd, J=11.7, 6.8 Hz, 1H), 3.25-3.31 (m, 2H),1.40-1.62 (m, 8H), 0.89 (t, J=7.0 Hz, 6H).

Step 4. A solution of alkynol 155 (0.59 g, 1.59 mmol) in NH₃/MeOH (7N,10 mL) and aqueous NH₄OH (25%, 10 mL) was stirred at room temperaturefor 70 hrs and the concentrated under reduced pressure. Purification byflash chromatography (0% to 100% of 10% 7N NH₃/MeOH/CH₂Cl₂ in CH₂Cl₂)gave amine 156 as a colorless oil. Yield (0.35 g, 80%); ¹H NMR (400 MHz,CD₃OD) δ 7.39-7.41 (m, 1H), 7.26-7.32 (m, 3H), 4.58 (dd, J=4.7, 7.6 Hz,1H), 2.65-2.81 (m, 2H), 1.51-1.73-9 m, 8H), 0.97 (t, J=7.0 Hz, 6H);143.7, 130.3, 128.9, 128.3, 125.8, 123.4, 92.4, 83.7, 74.5, 70.9, 49.0,44.5, 17.6, 13.6; LC-MS: 276.38 [M+H]+; RP-HPLC tR=6.21 min, 98% AUC.

Step 5: Hydrogenation of alkyne 156 followed by flash chromatographypurification (10% to 50% of 20% 7N NH₃/MeOH/CH₂Cl₂— CH₂Cl₂ gradient)gave Example 139 as a colorless oil. Yield (0.042 g, 57%); ¹H NMR (400MHz, CD₃OD) δ 7.23 (t, J=7.6 Hz, 1H), 7.07-7.21 (m, 3H), 4.58 (dd,J=5.1, 7.2 Hz, 1H), 2.72-2.82 (m, 2H), 2.61 (ddd, J=4.9, 8.6, 12.7 Hz,2H), 1.68 (ddd, J=4.7, 8.4, 12.5 Hz, 2H), 1.26-1.50 (m, 8H), 0.93 (t,J=7.2 Hz, 6H); LC-MS (ESI+) 280.41 [M+H]+; RP-HPLC (Method 2): 85.1%(AUC), t_(R)=6.17 min.

Example 140 Preparation of4-(5-(3-amino-1-hydroxypropyl)-2-fluorophenethyl)heptan-4-ol

4-(5-(3-Amino-1-hydroxypropyl)-2-fluorophenethyl)heptan-4-ol wasprepared following the method used in Examples 1, 7, 9, 16 and 17.

Step 1: Addition of acetonitrile to 3-bromo-4-fluorobenzaldehydefollowing the method used in Example 16 gave3-(3-bromo-4-fluorophenyl)-3-hydroxypropanenitrile as a pale yellow oil.Yield (4.2 g, 70%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (dd, J=6.8, 2.0 Hz,1H), 7.44 (ddd, J=8.4, 5.2, 2.4 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H), 6.08(bs, 1H), 4.90 (s, 1H), 2.90 (ABd, J=16.8, 5.2 Hz, 1H), 2.83 (ABd,J=16.8, 6.4 Hz, 1H).

Step 2: Reduction of 3-(3-bromo-4-fluorophenyl)-3-hydroxypropanenitrilewith BH₃-THF following the method used in Example 17, followed byprotection of the amine with ethyl trifluoroacetate following the methodused in Example 9 gaveN-(3-(3-bromo-4-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas a clear oil. Yield (4.3 g, 73%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.31(bs, 1H), 7.62 (dd, J=6.8, 2.0 Hz, 1H), 7.37-7.33 (m, 1H), 7.30 (t,J=8.8 Hz, 1H), 5.48 (d, J=4.4 Hz, 1H), 4.60-4.56 (m, 1H), 3.28-3.15 (m,2H), 1.84-1.71 (m, 2H).

Step 3:N-(3-(3-Bromo-4-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidewas coupled with 4-ethynylheptan-4-ol following the method used inExample 7 to give2,2,2-trifluoro-N-(3-(4-fluoro-3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)acetamideas a pale yellow oil. Yield (1.37 g, 78%): ¹H NMR (400 MHz, DMSO-d₆) δ9.31 (t, J=5.0 Hz, 1H), 7.37 (dd, J=6.8, 2.0 Hz, 1H), 7.34-7.30 (m, 1H),7.18 (t, J=9.0 Hz, 1H), 5.41 (d, J=4.8 Hz, 1H), 5.19 (s, 1H), 4.58-4.54(m, 1H), 3.28-3.16 (m, 2H), 1.82-1.69 (m, 2H), 1.63-1.41 (m, 8H), 0.89(t, J=7.2 Hz, 6H).

Step 4:2,2,2-Trifluoro-N-(3-(4-fluoro-3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)acetamidewas deprotected following the method used in Example 9 to give4-((5-(3-amino-1-hydroxypropyl)-2-fluorophenyl)ethynyl)heptan-4-ol as apale yellow oil. Yield (0.85 g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.35(dd, J=6.8, 2.0 Hz, 1H), 7.31-7.27 (m, 1H), 7.16 (t, J=9.0 Hz, 1H), 5.19(bs, 1H), 4.64 (t, J=6.4 Hz, 1H), 2.64-2.52 (m, 2H), 1.63-1.42 (m, 10H),0.89 (t, J=7.2 Hz, 6H).

Step 5:4-((5-(3-Amino-1-hydroxypropyl)-2-fluorophenyl)ethynyl)heptan-4-ol(0.107 g, 0.348 mmole) was dissolved in EtOAc (5 ml) and degassed with astream of argon. 10% Pd/C (10 mg) was added and a vacuum was pulled for1 min. A balloon of H₂ was added and stirred for 3 hr. Filtration of thecatalyst followed by evaporation to dryness gave Example 140 as a paleyellow oil. Yield (0.11 g, 100%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.17 (dd,J=7.6, 2.0 Hz, 1H), 7.13-7.09 (m, 1H), 7.00 (dd, J=10.0, 8.4 Hz, 1H),4.61 (m, 1H), 3.98 (bs, 1H), 2.63-2.56 (m, 2H), 2.54-2.50 (m, 2H),1.63-1.58 (m, 2H), 1.53-1.49 (m, 2H), 1.35-1.20 (m, 8H), 0.84 (t, J=7.0Hz, 6H).

Example 141 Preparation of(R)—N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propyl)acetamide

(R)—N-(3-Hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propyl)acetamidewas prepared following the method below.

Example 71 (0.35 g, 1.19 mmol) and acetic anhydride (0.13 g, 1.25 mmole)was stirred in CH₂Cl₂ overnight at room temperature. The reactionmixture was partitioned between CH₂Cl₂ and sat NaHCO₃. The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure to giveExample 141 as a clear oil. Yield (0.40 g, 100%); ¹H NMR (400 MHz,DMSO-d₆) δ 7.62 (t, =5.0 Hz, 1H), 7.17 (t, J=7.4 Hz, 1H), 7.11 (s, 1H),7.07 (d, J=8.0 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H). 5.14 (d, J=4.4 Hz, 1H),4.51-4.47 (m, 1H), 3.95 (s, 1H), 3.07-3.02 (m, 2H), 2.52-2.47 (m, 2H),1.76 (s, 3H), 1.65 (q, J=6.8 Hz, 2H), 1.56-1.51 (m, 2H), 1.35-1.21 (m,8H), 0.84 (t, J=7.0 Hz, 6H).

Example 142 Preparation of(R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propyl)acetamide

(R)-2,2,2-Trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propyl)acetamidewas prepared following the method below.

A mixture of Example 71 (0.29 g, 0.98 mmole) and CF₃CO₂Et (2 ml) inCH₂Cl₂ was stirred at room temperature overnight. Concentration underreduced pressure gave Example 142 as a clear oil. Yield (0.39 g, 100%);¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (t, =5.2 Hz, 1H), 7.18 (t, J=7.6 Hz,1H), 7.11 (s, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 5.25(bs, 1H), 4.52 (t, J=6.4 Hz, 1H), 3.94 (bs, 1H), 3.22 (q, J=6.8 Hz, 2H),2.52-2.47 (m, 2H), 1.79-1.73 (m, 2H), 1.56-1.51 (m, 2H), 1.35-1.21 (m,8H), 0.84 (t, J=7.0 Hz, 6H).

Example 143 Preparation of4-(3-(3-amino-2-hydroxypropyl)phenethyl)heptan-4-ol

4-(3-(3-Amino-2-hydroxypropyl)phenethyl)heptan-4-ol was preparedfollowing the method shown in Scheme 31.

Step 1: To a solution of 1-(3-bromophenyl)-3-chloropropan-2-ol (157)(8.49 g, 34.0 mmol) in anhydrous DMF (100 mL) under N₂ was added NaN₃(11.05 g, 170.0 mmol) and NaI (cat., 0.75 g, 5.0 mmol). The mixture washeated at 75° C. overnight. After cooling to room temperature, themixture was diluted with ether and washed with water and brine. Thesolution was dried over Na₂SO₄ and concentrated under reduced pressure.The product was dried in a vacuum oven at 40° C. for 2 h to give azide158 as a yellow oil which was used without purification. Yield (8.6 g,98% crude).

Step 2: To a solution of azide 158 (8.59 g, 33.28 mmol) in THF (60 mL)under N₂ was added PPh₃ (8.73 g, 33.28 mmol) and water (20 mL). Thereaction mixture was heated at 50° C. for 24 h. After cooling to roomtemperature, the mixture was diluted with brine and extracted withEtOAc. The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The crude amine was dissolved in THF (20 ml) and ethyltrifluoroacetate (20 ml) and stirred overnight at room temperature.Evaporation under reduced pressure followed by purification by flashchromatography (5% EtOAc/CH₂Cl₂) gave trifluoroacetamide 159 as a whitesolid. Yield (3.72 g, 35%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (t, J=5.2Hz, 1H), 7.42 (d, J=1.2 Hz, 1H), 7.38-7.35 (m, 1H), 7.24-7.20 (m, 2H),5.00 (d, J=6.0 Hz, 1H), 3.83-3.75 (m, 1H), 3.21-3.07 (m, 2H), 2.70 (dd,J=13.6 Hz, 4.8, 1H), 2.55 (dd, J=14.0, 6.0 Hz, 1H).

Step 3: Coupling of bromide 159 with 4-ethynylheptan-4-ol following theprocedure described in Example 7 gave alkyne 160 as a clear oil. Yield(0.455 g, 59%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (t, J=5.4 Hz, 1H),7.25-7.22 (m, 2H), 7.18-7.16 (m, 2H), 5.11 (s, 1H), 4.96 (d, J=5.6 Hz,1H), 3.81-3.74 (m, 1H), 3.21-3.07 (m, 2H), 2.68 (dd, J=14.0, 4.6 Hz,1H), 2.54 (dd, J=14.0, 7.8 Hz, 1H), 1.61-1.40 (m, 8H), 0.89 (t, J=7.2Hz, 6H).

Step 4: Deprotection of trifluoroacetamide 160 following the proceduredescribed in Example 9 gave amine 161 as a pale yellow oil. Yield (0.273g, 82%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.24-7.20 (m, 2H), 7.17-7.13 (m,2H), 5.11 (bs, 1H), 4.55 (bs, 1H), 3.51-3.46 (m, 1H), 2.67 (dd, J=13.6,5.2 Hz, 1H), 2.50 (dd, J=13.6, 7.6 Hz, 1H), 2.45 (dd, obs., 1H), 2.37(dd, J=12.8, 6.8 Hz, 1H), 1.61-1.40 (m, 8H), 0.89 (t, J=7.6 Hz, 6H).

Step 5: Hydrogenation of amine 161 following the method used in Example140 gave Example 143 as a pale yellow oil. Yield (0.10 g, 100%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.12 (t, J=7.4 Hz, 1H), 6.98-6.94 (m, 3H), 3.94(bs, 1H), 3.53-3.47 (m, 1H), 2.62 (dd, J=13.6, 5.6 Hz, 1H), 2.51 (dd,J=13.2, 7.2 Hz, 1H), 2.49-2.45 (m, obs., 3H), 2.37 (dd, J=12.8, 7.2 Hz,1H), 1.55-1.51 (m, 2H), 1.35-1.21 (m, 8H), 0.84 (t, J=7.0 Hz, 6H).

Example 144 Preparation of4-(5-(3-amino-1-hydroxypropyl)-2-methoxyphenethyl)heptan-4-ol

4-(5-(3-Amino-1-hydroxypropyl)-2-methoxyphenethyl)heptan-4-ol wasprepared following the method used in Example 140.

Step 1: Addition of acetonitrile to 3-bromo-4-methoxybenzaldehyde gave3-(3-bromo-4-methoxyphenyl)-3-hydroxypropanenitrile as a pale orangeoil. Yield (10.32 g, 96%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (d, J=2.0Hz, 1H), 7.35 (dd, J=8.8, 2.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 5.93 (d,J=4.4 Hz, 1H), 4.85-4.81 (m, 1H). 3.81 (s, 3H), 2.86 (ABd, J=16.4, 4.8Hz, 1H), 2.79 (ABd, J=16.8, 6.8 Hz, 1H).

Step 2: Reduction of 3-(3-bromo-4-methoxyphenyl)-3-hydroxypropanenitrilewith BH₃-THF followed by protection of the amine gaveN-(3-(3-bromo-4-methoxyphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas an orange oil. Yield (5.76 g, 40%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.31(bs, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.26 (dd, J=8.8, 2.0 Hz, 1H), 7.03 (d,J=8.8 Hz, 1H), 5.32 (d, J=4.8 Hz, 1H), 4.53-4.49 (m, 1H), 3.80 (s, 3H),3.24-3.15 (m, 2H), 1.79-1.72 (m, 2H).

Step 3:N-(3-(3-bromo-4-methoxyphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidewas coupled with 4-ethynylheptan-4-ol to give2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)-4-methoxyphenyl)propyl)acetamideas a yellow oil. Yield (0.92 g, 55%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.31(t, J=5.0 Hz, 1H), 7.24-7.21 (m, 2H), 6.95 (d, J=9.2 Hz, 1H), 5.25 (d,J=4.8 Hz, 1H), 5.05 (s, 1H), 4.51-4.47 (m, 1H), 3.75 (s, 3H), 3.24-3.17(m, 2H), 1.77-1.72 (m, 2H), 1.61-1.42 (m, 8H), 0.89 (t, J=7.0 Hz, 6H).

Step 4:2,2,2-Trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)-4-methoxyphenyl)propyl)acetamidewas deprotected to give4-((5-(3-amino-1-hydroxypropyl)-2-methoxyphenyl)ethynyl)heptan-4-ol as apale yellow oil. Yield (0.53 g, 76%): ¹H NMR (400 MHz, DMSO-d₆) δ7.22-7.19 (m, 2H), 6.92 (d, J=8.4 Hz, 1H), 5.06 (bs, 1H), 4.58-4.55 (m,1H), 3.74 (s, 3H), 2.63-2.51 (m, 2H), 1.64- 1.42 (m, 10H), 0.89 (t,J=7.0 Hz, 6H).

Step 5. Hydrogenation of4-((5-(3-amino-1-hydroxypropyl)-2-methoxyphenyl)ethynyl)heptan-4-olfollowing the method used in Example 140 gave Example 144 as a paleyellow oil. Yield (0.11 g, 100%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.05-7.02(m, 2H), 6.81 (d, J=8.0 Hz, 1H), 4.55-4.52 (m, 1H), 3.84 (bs, 1H), 3.71(s, 3H), 2.64-2.61 (m, 2H), 2.47-2.43 (m, 2H), 1.65-1.53 (m, 2H),1.50-1.45 (m, 2H), 1.39-1.21 (m, 8H), 0.85 (t, J=6.8 Hz, 6H).

Example 145 Preparation of4-(5-(3-amino-1-hydroxypropyl)-2-methylphenethyl)heptan-4-ol

4-(5-(3-Amino-1-hydroxypropyl)-2-methylphenethyl)heptan-4-ol wasprepared following the method used in Example 140.

Step 1: Alkylation of 3-bromo-4-methylbenzaldehyde with acetonitrilegave 3-(3-bromo-4-methylphenyl)-3-hydroxypropanenitrile as a pale yellowoil. Yield (5.1 g, 94%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (d, J=1.2 Hz,1H), 7.31 (d, J=8.0 Hz, 1H), 7.28 (dd, J=8.0 Hz, 1.2, 1H), 5.99 (d,J=4.8 Hz, 1H), 4.87-4.84 (m, 1H), 2.88 (ABd, J=16.8, 4.8 Hz, 1H), 2.80(ABd, J=16.8, 6.8 Hz, 1H), 2.30 (s, 3H).

Step 2: Reduction of 3-(3-bromo-4-methylphenyl)-3-hydroxypropanenitrilewith BH₃-THF followed by protection of the amine gaveN-(3-(3-bromo-4-methylphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas a clear oil. Yield (4.12 g, 57%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.31(bs, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.20 (dd,J=8.4, 1.6 Hz, 1H), 5.38 (d, J=4.4 Hz, 1H), 4.56-4.52 (m, 1H), 3.28-3.14(m, 2H), 2.25 (s, 3H), 1.83-1.75 (m, 2H).

Step 3:N-(3-(3-Bromo-4-methylphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidewas coupled with 4-ethynylheptan-4-ol to give2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)-4-methylphenyl)propyl)acetamideas a yellow oil. Yield (0.286 g, 28%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.31(t, J=5.2 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.16 (dd,J=7.6, 1.8 Hz, 1H), 5.30 (d, J=4.8 Hz, 1H), 5.10 (s, 1H), 4.54-4.50 (m,1H), 3.25-3.14 (m, 2H), 2.30 (s, 3H), 1.78-1.72 (m, 2H), 1.63-1.36 (m,8H), 0.89 (t, J=7.2 Hz, 6H).

Step 4:2,2,2-Trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)-4-methylphenyl)propyl)acetamidewas deprotected to give4-((5-(3-amino-1-hydroxypropyl)-2-methylphenyl)ethynyl)heptan-4-ol as apale yellow oil. Yield (0.161 g, 76%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.25(s, 1H), 7.17-7.12 (m, 2H), 5.11 (bs, 1H), 4.59 (t, J=6.4 Hz, 1H),2.64-2.52 (m, 2H), 2.30 (s, 3H), 1.73-1.42 (m, 10H), 0.89 (t, J=7.2 Hz,6H)

Step 5: Hydrogenation of4-((5-(3-amino-1-hydroxypropyl)-2-methylphenyl)ethynyl)heptan-4-ol gaveExample 145 as a pale yellow oil. Yield (0.11 g, 100%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.02-6.99 (m, 2H), 6.96 (dd, J=8.0, 1.6 Hz, 1H), 4.57-4.54(m, 1H), 3.96 (bs, 1H), 2.65-2.54 (m, 2H), 2.50-2.47 (m, obs., 2H), 2.19(s, 3H), 1.63-1.53 (m, 2H), 1.47-1.43 (m, 2H), 1.37-1.22 (m, 8H), 0.86(t, J=7.2 Hz, 6H).

Example 146 Preparation of4-(3-(3-amino-1-hydroxypropyl)-5-methoxyphenethyl)heptan-4-ol

4-(3-(3-Amino-1-hydroxypropyl)-5-methoxyphenethyl)heptan-4-ol wasprepared following the method used in Example 140.

Step 1: Alkylation of 3-bromo-5-methoxybenzaldehyde with acetonitrilegave 3-(3-bromo-5-methoxyphenyl)-3-hydroxypropanenitrile as a paleyellow oil. Yield (4.1 g, 70%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.16-7.15(m, 1H), 7.04-7.03 (m, 1H), 6.97-6.96 (m, 1H), 6.04 (d, J=4.8 Hz, 1H),4.87-4.83 (m, 1H), 3.74 (s, 3H), 2.89 (ABd, J=16.4, 5.2 Hz, 1H), 2.81(ABd, J=16.8, 6.8 Hz, 1H).

Step 2: Reduction of 3-(3-bromo-5-methoxyphenyl)-3-hydroxypropanenitrilewith BH₃-THF followed by protection of the amine gaveN-(3-(3-bromo-5-methoxyphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas a clear oil. Yield (3.9 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.30(bs, 1H), 7.07 (t, J=1.2 Hz, 1H), 6.98-6.97 (m, 1H), 6.88-6.87 (m, 1H),5.44 (d, J=4.8 Hz, 1H), 4.56-4.51 (m, 1H), 3.74 (m, 3H), 3.27-3.15 (m,2H), 1.96-1.70 (m, 2H).

Step 3:N-(3-(3-Bromo-5-methoxyphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidewas coupled with alkynol 20 to give2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)-5-methoxyphenyl)propyl)acetamideas a pale yellow oil. Yield (0.96 g, 66%): ¹H NMR (400 MHz, DMSO-d₆) δ9.31 (t, J=4.8 Hz, 1H), 6.91 (s, 1H), 6.86-6.85 (m, 1H), 6.73-6.72 (m,1H), 5.36 (d, J=4.8 Hz, 1H), 5.11 (s, 1H), 4.55-4.50 (m, 1H), 3.73 (s,3H), 3.27-3.16 (m, 2H), 1.81-1.69 (m, 2H), 1.61-1.39 (m, 8H), 0.89 (t,J=7.2 Hz, 6H).

Step 4:2,2,2-Trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)-5-methoxyphenyl)propyl)acetamidewas deprotected to give4-((3-(3-amino-1-hydroxypropyl)-5-methoxyphenyl)ethynyl)heptan-4-ol as apale yellow oil. Yield (0.63 g, 86%: ¹H NMR (400 MHz, DMSO-d₆) δ 6.89(s, 1H), 6.84-6.83 (m, 1H), 6.70-6.69 (m, 1H), 5.12 (bs, 1H), 4.60 (t,J=6.2 Hz, 1H), 3.72 (s, 3H), 2.60-2.53 (m, 2H), 1.61-1.39 (m, 10H), 0.89(t, J=7.2 Hz, 6H).

Step 5: Hydrogenation of4-((5-(3-amino-1-hydroxypropyl)-2-methylphenyl)ethynyl)heptan-4-ol gaveExample 146 as a pale yellow oil. Yield (0.10 g, 100%): ¹H NMR (400 MHz,DMSO-d₆) δ 6.81 (s, 1H), 6.65 (s, 1H), 6.54 (s, 1H), 4.56 (t, J=6.4 Hz,1H), 3.94 (bs, 1H), 3.69 (s, 3H), 2.66-2.58 (m, 2H), 2.48-2.44 (m, obs.,2H), 1.60 (q, J=6.8 Hz, 2H), 1.55-1.51 (m, 2H), 1.34-1.22 (m, 8H), 0.84(t, J=7.2 Hz, 6H).

Example 147 Preparation of4-(3-(3-amino-1-hydroxypropyl)-4-chlorophenethyl)heptan-4-ol

4-(3-(3-Amino-1-hydroxypropyl)-4-chlorophenethyl)heptan-4-ol wasprepared following the method used in Example 140:

Step 1: Alkylation of 5-bromo-2-chlorobenzaldehyde with acetonitrilegave 3-(5-bromo-2-chlorophenyl)-3-hydroxypropanenitrile as a pale yellowliquid. Yield (4.42 g, 75%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.74 (d, J=2.8Hz, 1H), 7.53 (dd, J=8.8, 2.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 6.30 (d,J=4.8 Hz, 1H), 5.13-5.09 (m, 1H), 2.96 (ABd, J=16.8, 4.8 Hz, 1H), 2.83(ABd, J=17.0, 6.0 Hz, 1H).

Step 2: Reduction of 3-(5-bromo-2-chlorophenyl)-3-hydroxypropanenitrilewith BH₃-THF followed by protection of the amine gaveN-(3-(5-bromo-2-chlorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas an orange oil. Yield (2.6 g, 43%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.42(bs, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 7.33 (d,J=8.8 Hz, 1H), 5.64 (d, J=4.4 Hz, 1H), 3.33-3.29 (m, 2H), 1.96-1.80 (m,1H), 1.68-1.59 (m, 1H).

Step 3:N-(3-(5-Bromo-2-chlorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidewas coupled with 4-ethynylheptan-4-ol to giveN-(3-(2-chloro-5-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas a pale yellow oil. Yield (1.03 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ9.42 (t, J=5.6 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H),7.23 (dd, J=8.0 Hz, 2.0, 1H), 5.57 (d, J=4.0 Hz, 1H), 5.17 (s, 1H),4.87-4.82 (m, 1H), 3.33-3.28 (m, 2H), 1.87-1.79 (m, 1H), 1.66-1.39 (m,9H), 0.89 (t, J=7.2 Hz, 6H).

Step 4:N-(3-(2-Chloro-5-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidewas deprotected to give4-((3-(3-amino-1-hydroxypropyl)-4-chlorophenyl)ethynyl)heptan-4-ol as apale yellow oil. Yield (0.77 g, 98%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.53(d, J=2.4 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.23 (dd, JJ=8.0, 2.4 Hz,1H), 5.17 (bs, 1H), 4.93 (dd, J=8.8, 2.4 Hz, 1H), 2.72-2.63 (m, 2H),1.70-1.62 (m, 1H), 1.59-1.39 (m, 9H), 0.89 (t, J=7.2 Hz, 6H).

Step 5: Hydrogenation of4-((3-(3-amino-1-hydroxypropyl)-4-chlorophenyl)ethynyl)heptan-4-olfollowing the method used in Example 140 gave Example 147 as a paleyellow oil. Yield (0.11 g, 100%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.37 (d,J=2.4 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.03 (dd, J=8.0, 2.4 Hz, 1H),4.94-4.91 (m, 1H), 3.99 (bs, 1H), 2.72 (t, J=7.0 Hz, 2H), 2.53-2.49 (m,2H), 1.74-1.66 (m, 1H), 1.58-1.49 (m, 3H), 1.35-1.20 (m, 8H), 0.84 (t,J=6.8 Hz, 6H).

Example 148 Preparation of4-(3-(3-amino-1-hydroxypropyl)-4-methylphenethyl)heptan-4-ol

4-(3-(3-Amino-1-hydroxypropyl)-4-methylphenethyl)heptan-4-ol wasprepared following the method used in Example 140:

Step 1: Addition of 5-bromo-2-methylbenzaldehyde to acetonitrile gave3-(5-bromo-2-methylphenyl)-3-hydroxypropanenitrile as a pale yellow oil.Yield (3.33 g, 86%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.61 (d, J=2.0 Hz, 1H),7.35 (dd, J=8.0, 2.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.96 (d, J=4.4 Hz,1H), 5.04-5.00 (m, 1H), 2.88 (ABd, J=16.8, 4.4 Hz, 1H), 2.77 (ABd,J=16.8, 6.4 Hz, 1H), 2.23 (s, 3H).

Step 2: Reduction of 3-(3-bromo-2-methylphenyl)-3-hydroxypropanenitrilewith BH₃-THF followed by protection of the amine gaveN-(3-(3-bromo-2-methylphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas a pale yellow oil. Yield (3.25 g, 69%): ¹H NMR (400 MHz, DMSO-d₆) δ9.38 (bs, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.28 (dd, J=8.0, 2.4 Hz, 1H),7.05 (d, J=8.0 Hz, 1H), 4.73-4.70 (m, 1H), 3.36-3.26 (m, 2H), 2.17 (s,3H), 1.79-1.71 (m, 1H), 1.68-1.59 (m, 1H).

Step 3:N-(3-(3-Bromo-2-methylphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidewas coupled with 4-ethynylheptan-4-ol to give2,2,2-trifluoro-N-(3-hydroxy-3-(5-(3-hydroxy-3-propylhex-1-ynyl)-2-methylphenyl)propyl)acetamideas a yellow oil. Yield (1.11 g, 62%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.38(t, J=5.2 Hz, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.11 (dd, J=8.0, 1.6 Hz, 1H),7.07 (d, J=8.0 Hz, 1H), 5.26 (d, J=4.4 Hz, 1H), 5.08 (s, 1H), 4.74-4.70(m, 1H), 3.35-3.25 (m, 2H), 2.21 (s, 3H), 1.78-1.70 (m, 2H), 1.68-1.40(m, 8H), 0.89 (t, J=7.2 Hz, 6H)

Step 4:2,2,2-Trifluoro-N-(3-hydroxy-3-(5-(3-hydroxy-3-propylhex-1-ynyl)-2-methylphenyl)propyl)acetamidewas deprotected to give4-((3-(3-amino-1-hydroxypropyl)-4-methylphenyl)ethynyl)heptan-4-ol as apale yellow oil. Yield (0.71 g, 85%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.41(d, J=1.6 Hz, 1H), 7.08 (dd, J=7.6, 1.4 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H),5.09 (bs, 1H), 4.83-4.80 (m, 1H), 2.72-2.61 (m, 2H), 2.23 (s, 3H),1.61-1.41 (m, 10H), 0.89 (t, J=7.0 Hz, 6H).

Step 5: Hydrogenation of4-((3-(3-amino-1-hydroxypropyl)-4-methylphenyl)ethynyl)heptan-4-olfollowing the method used in Example 140 gave Example 148 as a paleyellow oil. Yield (0.11 g, 100%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (d,J=1.6 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.87 (dd, J=7.6, 1.6 Hz, 1H),4.82-4.78 (m, 1H), 3.94 (bs, 1H), 2.74-2.64 (m, 2H), 2.47-2.43 (m, obs.,2H), 2.18 (s, 3H), 1.59-1.49 (m, 4H), 1.34-1.22 (m, 8H), 0.84 (t, J=7.0Hz, 6H).

Example 149 Preparation of1-(3-(3-amino-2-hydroxypropyl)phenyl)-3-ethylpentan-3-OL

1-(3-(3-Amino-2-hydroxypropyl)phenyl)-3-ethylpentan-3-ol was preparedfollowing the method used in Example 143.

Step 1: Coupling of bromide 159 with 3-ethylpent-1-yn-3-ol gaveN-(3-(3-(3-ethyl-3-hydroxypent-1-ynyl)phenyl)-2-hydroxypropyl)-2,2,2-trifluoroacetamideas a clear oil. Yield (0.472 g, 66%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.32(t, J=5.6 Hz, 1H), 7.26-7.22 (m, 2H), 7.20-7.16 (m, 2H), 5.11 (s, 1H),4.96 (d, J=5.6 Hz, 1H), 3.80-3.74 (m, 1H), 3.21-3.07 (m, 2H), 2.68 (dd,J=14.0, 4.8 Hz, 1H), 2.53 (dd, J=13.6, 7.6 Hz, 1H), 1.66-1.52 (m, 4H),0.96 (t, J=7.2 Hz, 6H).

Step 2: Deprotection ofN-(3-(3-(3-ethyl-3-hydroxypent-1-ynyl)phenyl)-2-hydroxypropyl)-2,2,2-trifluoroacetamidegaveN-(3-(3-(3-ethyl-3-hydroxypent-1-ynyl)phenyl)-2-hydroxypropyl)-2,2,2-trifluoroacetamideas a pale yellow oil. Yield (0.232 g, 69%): ¹H NMR (400 MHz, DMSO-d₆) δ7.24-7.20 (m, 2H), 7.17-7.15 (m, 2H), 5.11 (bs, 1H), 4.55 (bs, 1H),3.51-3.45 (m, 1H), 2.67 (dd, J=13.6, 5.2 Hz, 1H), 2.51 (dd, J=13.6, 7.6Hz, 1H), 2.45 (obs dm, J=4 4 Hz, 1H), 2.37 (dd, J=12.8, 6.8 Hz, 1H),1.66-1.52 (m, 4H), 0.96 (t, J=7.2 Hz, 6H).

Step 3: Hydrogenation ofN-(3-(3-(3-ethyl-3-hydroxypent-1-ynyl)phenyl)-2-hydroxypropyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 140 gave Example 149 as a paleyellow oil. Yield (0.83 g, 100%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.12 (t,J=7.6 Hz, 1H), 6.99 (s, 1H), 6.97-6.95 (m, 2H), 3.91 (bs, 1H), 3.54-3.47(m, 1H), 2.62 (dd, J=13.6, 5.6 Hz, 1H), 2.53 (dd, obs., 1H), 2.48-2.45(m, obs., 3H), 2.37 (dd, J=12.8, 7.2 Hz, 1H), 1.54-1.50 (m, 2H), 1.37(q, J=7.6 Hz, 4H), 0.79 (t, J=7.6 Hz, 6H).

Example 150 Preparation of1-(3-(3-amino-2-hydroxypropyl)phenethyl)cyclopentanol

1-(3-(3-Amino-2-hydroxypropyl)phenethyl)cyclopentanol was preparedfollowing the method used in Example 149:

Step 1: Coupling of bromide 159 with 1-ethynylcyclopentanol gave2,2,2-trifluoro-N-(2-hydroxy-3-(3-((1-hydroxycyclopentyl)ethynyl)phenyl)propyl)acetamideas a clear oil. Yield (0.441 g, 62%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.32(t, J=5.6 Hz, 1H), 7.26-7.22 (m, 2H), 7.19-7.16 (m, 2H), 5.26 (bs, 1H),4.97 (bs, 1H), 3.78 (bs, 1H), 3.20-3.06 (m, 2H), 2.67 (dd, J=14.0, 4.8Hz, 1H), 2.53 (dd, J=13.6, 7.6 Hz, 1H), 1.91-1.79 (m, 4H), 1.76-1.60 (m,4H).

Step 2: Deprotection of2,2,2-trifluoro-N-(2-hydroxy-3-(3-((1-hydroxycyclopentyl)ethynyl)phenyl)propyl)acetamidegave 1-((3-(3-amino-2-hydroxypropyl)phenyl)ethynyl)cyclopentanol as apale yellow solid. Yield (0.217 g, 69%): ¹H NMR (400 MHz, DMSO-d₆) δ7.24-7.20 (m, 2H), 7.17-7.15 (m, 2H), 5.26 (bs, 1H), 4.55 (bs, 1H),3.51-3.45 (m, 1H), 2.66 (dd, J=13.6, 5.2 Hz, 1H), 2.51 (dd, J=13.6, 8.0Hz, 1H), 2.45 (obs dm, J=4 4 Hz, 1H), 2.36 (dd, J=12.8, 6.8 Hz, 1H),1.91-1.80 (m, 4H), 1.76-1.60 (m, 4H).

Step 3: Hydrogenation of1-((3-(3-amino-2-hydroxypropyl)phenyl)ethynyl)cyclopentanol gave Example150 as a pale yellow oil. Yield (0.11 g, 100%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.12 (t, J=7.4 Hz, 1H), 7.00 (s, 1H), 6.97-6.95 (m, 2H), 4.07(bs, 1H), 3.57-3.45 (m, 1H), 2.62-2.58 (m, 3H), 2.52 (dd, J=13.2, 7.2Hz, 1H), 2.49 (dd, obs., 1H), 2.36 (dd, J=12.8, 6.8 Hz, 1H), 1.72-1.67(m, 4H), 1.57-1.40 (m, 6H).

Example 151 Preparation of1-(3-(3-aminopropyl)phenyl)-2-cyclohexylethanone

1-(3-(3-Aminopropyl)phenyl)-2-cyclohexylethanone was prepared followingthe method shown in Scheme 32.

Step 1: Bromomethylcyclohexane (5.26 g, 29.7 mmoles) was added underargon to Mg turnings (0.72 g, 29.7 mmoles) in anhydrous THF containing acrystal of I₂. The mixture was refluxed under an argon atmosphere for 3hrs, cooled to room temperature and added via syringe to a stirringsolution of 3-bromobenzaldehyde (30) (5.0 g, 27.0 mmoles) in anhydrousTHF cooled to 0° C. The reaction mixture was stirred at room temperatureovernight and partitioned between sat. NH₄Cl and EtOAc. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. Purification by flash chromatography (10% EtOAc/hexanes) gavealcohol 162 as a clear oil. Yield (2.72 g, 36%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.47 (t, J=1.6 Hz, 1H), 7.37 (dt, J=7.2, 2.0 Hz, 1H),7.28-7.21 (m, 2H), 5.17 (d, J=5.2 Hz, 1H), 4.59-4.54 (m, 1H), 1.76 (d,J=12.8 Hz, 1H), 1.64-1.56 (m, 4H), 1.49-1.27 (m, 3H), 1.21-1.06 (m, 3H),0.93-0.80 (m, 2H).

Step 2: Heck coupling of bromide 162 and tert-butyl prop-2-ynylcarbamatefollowing the method used in Example 154 gave (E)-alkene 163 as a clearoil. Yield (0.207 g, 48%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.29 (s, 1H),7.24-7.19 (m, 2H), 7.14-7.12 (m, 1H), 7.14 (t, J=5.6 Hz, 1H), 6.41 (d,J=16.0 Hz, 1H), 6.16 (dt, J=16.0, 5.6 Hz, 1H), 5.01 (d, J=4.4 Hz, 1H),4.57-4.53 (m, 1H), 3.69 (t, J=5.2 Hz, 2H), 1.74 (d, J=12.8 Hz, 1H),1.66-1.42 (m, 5H), 1.40-1.28 (m, 11H), 1.21-1.04 (m, 3H), 0.92-0.84 (m,2H).

Step 3: Hydrogenation of (E)-alkene 163 following the method used inExample 2 except that the reaction was carried out in EtOAc gave alkane164 as a clear oil. Yield (0.197 g, 100%): ¹H NMR (400 MHz, DMSO-d₆) δ7.17 (t, =7.2 Hz, 1H), 7.11-7.06 (m, 2H), 6.99 (d, J=7.6 Hz, 1H), 6.82(t, J=5.2 Hz, 1H), 4.96 (d, J=4.4 Hz, 1H), 4.55-4.51 (m, 1H), 2.90 (m,2H), 2.52-2.46 (m, obs., 2H), 1.74 (d, J=12.4 Hz, 1H), 1.66-1.51 (m,6H), 1.50-1.43 (m, 1H), 1.40-1.27 (m, 11H), 1.21-1.06 (m, 3H), 0.91-0.82(m, 2H).

Step 4: PCC oxidation of alcohol 164 following the method used inExample 70 gave ketone 165 as a clear oil. Yield (0.134 g, 74%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.75-7.72 (m, 2H), 7.43 (dt, J=8.0, 1.6 Hz, 1H),7.39 (t, J=7.6 Hz, 1H), 6.84 (t, J=5.2 Hz, 1H), 2.93-2.88 (m, 2H), 2.84(d, J=6.4 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.86-1.77 (m, 1H), 1.70-1.56(m, 7H), 1.35 (s, 9H), 1.24-1.07 (m, 3H), 1.00-0.91 (m, 2H).

Step 5: tert-Butyl 3-(3-(2-cyclohexylacetyl)phenyl)propylcarbamate (165)(0.124 g, 0.345 mmole) was dissolved in EtOAc and cooled in an ice bath.HCl gas was bubbled into the solution for 2 min. and allowed to stir at0° C. for 2 hr. The white precipitate was collected by filtration,washed with EtOAc and dried in vacuo to give Example 153 hydrochlorideas a white solid. Yield (0.7 g, 69%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.95(br.s, 3H), 7.80-7.77 (m, 2H), 7.48-7.41 (m, 2H), 2.84 (d, J=6.8 Hz,2H), 2.77-2.68 (m, 4H), 1.89-1.77 (m, 3H), 1.66-1.56 (m, 5H), 1.25-1.05(m, 3H), 1.01-0.91 (m, 2H).

Example 152 Preparation of1-(3-(3-amino-2-hydroxypropyl)phenethyl)cyclohexanol

1-(3-(3-Amino-2-hydroxypropyl)phenethyl)cyclohexanol was preparedfollowing the method used in Example 149.

Step 1: Coupling of bromide 159 with 1-ethynylcyclohexanol gave2,2,2-trifluoro-N-(2-hydroxy-3-(3-((1-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamideas a clear oil. Yield (0.48 g, 65%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.32(t, J=5.6 Hz, 1H), 7.26-7.22 (m, 2H), 7.20-7.16 (m, 2H), 5.37 (s, 1H),4.97 (d, J=5.6 Hz, 1H), 3.82-3.75 (m, 1H), 3.21-3.07 (m, 2H), 2.66 (dd,J=14.0, 4.8 Hz, 1H), 2.55 (dd, J=13.6, 7.8 Hz, 1H), 1.83-1.79 (m, 2H),1.63-1.60 (m, 2H), 1.54-1.44 (m, 5H), 1.23-1.18 (m, 1H).

Step 2: Deprotection of2,2,2-trifluoro-N-(2-hydroxy-3-(3-((1-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamidegave 1-((3-(3-amino-2-hydroxypropyl)phenyl)ethynyl)cyclohexanol as apale yellow solid. Yield (0.227 g, 65%): ¹H NMR (400 MHz, DMSO-d₆) δ7.25-7.21 (m, 2H), 7.18-7.15 (m, 2H), 5.37 (bs, 1H), 4.59 (bs, 1H),3.53-3.47 (m, 1H), 2.67 (dd, J=13.6, 5.2 Hz, 1H), 2.51 (dd, J=13.6, 7.6Hz, 1H), 2.48 (obs m, 1H), 2.38 (dd, J=12.8, 6.8 Hz, 1H), 1.83-1.77 (m,2H), 1.63-1.60 (m, 2H), 1.54-1.45 (m, 5H), 1.23-1.18 (m, 1H).

Step 3: Hydrogenation of1-((3-(3-amino-2-hydroxypropyl)phenyl)ethynyl)cyclohexanol gave Example152 as a pale yellow oil. Yield (0.12 g, 100%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.12 (t, J=7.2 Hz, 1H), 6.99-6.94 (m, 3H), 3.96 (bs, 1H),3.53-3.47 (m, 1H), 2.61 (dd, J=13.2, 5.6 Hz, 1H), 2.61-2.46 (m, obs.,4H), 2.37 (dd, J=12.8, 7.2 Hz, 1H), 1.59-1.51 (m, 4H), 1.48-1.40 (m,3H), 1.37-1.27 (m, 4H), 1.23-1.15 (m, 1H).

Example 153 Preparation of2-(3-(3-aminopropyl)phenyl)-1-cyclohexylethanone

2-(3-(3-Aminopropyl)phenyl)-1-cyclohexylethanone was prepared followingthe method used in Example 151.

Step 1: Grignard reaction between cyclohexanecarbaldehyde and3-bromobenzyl magnesium bromide (0.25M in ether) gave2-(3-bromophenyl)-1-cyclohexylethanol as a white solid. Yield (1.62 g,23%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (d, J=0.8 Hz, 1H), 7.34-7.31 (m,1H), 7.20-7.17 (m, 2H), 4.37 (d, J=6.0 Hz, 1H), 3.38-3.32 (m, 1H), 2.69(dd, J=13.6, 3.6 Hz, 1H), 2.51-2.45 (dd, obs., 1H), 1.78-1.60 (m, 5H),1.24-0.94 (m, 6H).

Step 2: Heck coupling of 2-(3-bromophenyl)-1-cyclohexylethanol andtert-butyl prop-2-ynylcarbamate gave (E)-tert-butyl3-(3-(2-cyclohexyl-2-hydroxyethyl)phenyl)allylcarbamate as a clear oil.Yield (0.362 g, 45%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.20 (s, 1H),7.18-7.14 (m, 2H), 7.05-7.03 (m, 2H), 6.38 (d, J=16.0 Hz, 1H), 6.14 (dt,J=16.0, 5.8 Hz, 1H), 4.29 (d, J=6.0 Hz, 1H), 3.68 (t, J=6.2 Hz, 2H),2.67 (dd, J=13.6, 4.4 Hz, 1H), 2.50 (dd, obs., 1H), 1.78-1.57 (m, 5H),1.37 (s, 9H), 1.21-0.99 (m, 6H).

Step 3: Hydrogenation of (E)-tert-butyl3-(3-(2-cyclohexyl-2-hydroxyethyl)phenyl)allylcarbamate gave tert-butyl3-(3-(2-cyclohexyl-2-hydroxyethyl)phenyl)propylcarbamate as a clear oil.Yield (0.356 g, 100%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.12 (t, J=7.4, 1H),6.99-6.94 (m, 3H), 6.82 (t, J=5.2 Hz, 1H), 4.26 (d, J=5.6 Hz, 1H),3.40-3.34 (m, 1H), 2.89 (q, J=6.6 Hz, 2H), 2.64 (dd, J=13.6, 4.4 Hz,1H), 2.50 (m, obs., 3H), 1.78-1.58 (m, 7H), 1.35 (s, 9H), 1.19-0.96 (m,6H).

Step 4: PCC oxidation of tert-butyl3-(3-(2-cyclohexyl-2-hydroxyethyl)phenyl)propylcarbamate gave tert-butyl3-(3-(2-cyclohexyl-2-oxoethyl)phenyl)propylcarbamate as a clear oil.Yield (0.254 g, 73%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.17 (t, J=7.6 Hz,1H), 7.02 (d, J=8.0 Hz, 1H), 6.93-6.93 (m, 2H), 6.82 (t, J=5.2 Hz, 1H),3.73 (s, 2H), 2.89 (q, J=6.4 Hz, 2H), 2.51-2.42 (m, obs., 3H), 1.77-1.74(m, 2H), 1.67-1.56 (m, 5H), 1.35 (s, 9H), 1.20-1.08 (m, 5H).

Step 5: Deprotection of tert-butyl3-(3-(2-cyclohexyl-2-oxoethyl)phenyl)propylcarbamate gave Example 153hydrochloride as an off-white solid. Yield (0.162 g, 80%): ¹H NMR (400MHz, DMSO-d₆) δ 8.04 (br.s, 3H), 7.20 (t, J=7.6 Hz, 1H), 7.05 (d, J=8.0Hz, 1H), 6.98-6.96 (m, 2H), 3.75 (s, 2H), 2.76-2.69 (m, 2H), 2.59 (t,J=7.8 Hz, 2H), 2.49-2.43 (m, obs, 1H), 1.85-1.75 (m, 4H), 1.69-1.65 (m,2H), 1.59-1.56 (m, 1H), 1.27-1.08 (m, 5H).

Example 154 Preparation of1-(3-(3-amino-1-hydroxypropyl)-5-fluorophenethyl)cyclohexanol

1-(3-(3-Amino-1-hydroxypropyl)-5-fluorophenethyl)cyclohexanol wasprepared following the method used in Examples 2, 16, 17, 19 and 118.

Step 1: Reaction of 3-bromo-5-fluorobenzaldehyde with acetonitrilefollowing the method described in Example 16 gave3-bromo-5-fluorobenzaldehyde as a pale yellow oil. Yield (2.5 g, 86%):¹H NMR (400 MHz, CDCl₃) δ 7.34 (t, J=1.6 Hz, 1H), 7.23 (dt, J=8.0, 1.6Hz, 1H), 7.08-7.11 (m, 1H), 5.03 (t, J=6.4 Hz, 1H), 2.75 (d, J=6.0 Hz,2H).

Step 2: Reduction of 3-bromo-5-fluorobenzaldehyde usingborane-dimethylsulfide complex following the method described in Example17, followed by protection with ethyl trifluoroacetate following themethod described in Example 19 gaveN-(3-(3-bromo-5-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas a light yellow oil. Yield (1.0 g, 30%): ¹H NMR (400 MHz, DMSO-d₆) δ9.30 (t, J=5.6 Hz, 1H), 7.34-7.38 (m, 2H), 7.17 (dt, J=9.6, 1.6 Hz, 1H),5.57 (d, J=4.4 Hz, 1H), 4.57-4.62 (m, 1H), 3.14-3.30 (m, 2H), 1.70-1.86(m, 2H).

Step 3: A mixture ofN-(3-(3-bromo-5-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide(0.58 g, 1.57 mmol), 1-vinylcyclohexanol (0.3 g, 2.38 mmol) andpalladium acetate (0.03 g, 0.12 mmol) in tetrabutyl ammonium acetate(1.0 g) and DMF (1 ml) was heated at 90° C. for 1 h. After cooled toroom temperature, the reaction mixture was partitioned between water (40ml) and ethyl acetate (60 ml). Ethyl acetate portion was dried overNa₂SO₄. Purification by chromatography (40 to 60% EtOAc-hexanesgradient) gave(E)-2,2,2-trifluoro-N-(3-(3-fluoro-5-(2-(1-hydroxycyclohexyl)vinyl)phenyl)-3-hydroxypropyl)acetamideas a colorless oil. Yield (0.25 g, 54%): H NMR (400 MHz, DMSO-d₆) δ 9.32(t, J=5.6 Hz, 1H), 6.94-7.18 (m, 3H), 6.41-6.53 (m, 2H), 5.42 (d, J=4.4Hz, 1H), 4.54-4.60 (m, 1H), 3.18-3.26 (m, 2H), 1.72-1.86 (m, 2H),1.38-1.66 (m, 10H).

Step 4: Deprotection of(E)-2,2,2-trifluoro-N-(3-(3-fluoro-5-(2-(1-hydroxycyclohexyl)vinyl)phenyl)-3-hydroxypropyl)acetamidefollowing method described in Example 2 gave(E)-1-(3-(3-amino-1-hydroxypropyl)-5-fluorostyryl)cyclohexanol as acolorless oil. Yield (0.065 g, 43%): ¹H NMR (400 MHz, MeOD) δ 7.19 (s,1H), 7.00 (dt, J=9.6, 2.0 Hz, 1H), 6.94 (dt, J=9.6, 1.6 Hz, 1H), 6.58(d, J=16.4 Hz, 1H), 6.39 (d, J=16.4 Hz, 1H), 4.72 (t, J=6.0 Hz, 1H),2.70-2.80 (m, 2H), 1.50-1.88 (m, 10H).

Step 5: Hydrogenation of(E)-1-(3-(3-amino-1-hydroxypropyl)-5-fluorostyryl)cyclohexanol followingmethod described in Example 2 gave Example 154 as a pale yellow oilwhich was dissolved in MeOH and treated with HCl/EtOH. The mixture wasconcentrated under reduced pressure, the residue was resuspended inEtOAc and the solids were collected by filtration to give Example 154hydrochloride as a white solid. Yield (0.05 g, 90%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.88 (bs, 3H), 6.98 (s, 1H), 6.86-6.93 (m, 2H), 5.60 (d,J=4.0 Hz, 1H), 4.66 (t, J=4.0 Hz, 1H), 2.74-2.84 (m, 2H), 2.58-2.62 (m,2H), 1.72-1.90 (m, 2H), 1.10-1.58 (m, 13H).

Example 155 Preparation of1-(3-(3-amino-1-hydroxypropyl)-2-fluorophenethyl)cyclohexanol

1-(3-(3-Amino-1-hydroxypropyl)-2-fluorophenethyl)cyclohexanol wasprepared following the method used in Example 154.

Step 1: Reaction of 3-bromo-2-fluorobenzaldehyde with acetonitrile gave3-(3-bromo-2-fluorophenyl)-3-hydroxypropanenitrile as a light yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 7.54 (t, J=7.2 Hz, 2H), 7.11 (td, J=7.6,0.4 Hz, 1H), 5.37 (dd, J=6.8, 4.4 Hz, 1H), 2.73-2.91 (m, 2H).

Step 2: Reduction of 3-(3-bromo-2-fluorophenyl)-3-hydroxypropanenitrileusing borane-dimethylsulfide complex gaveN-(3-(3-bromo-2-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideas a light yellow oil. Yield (0.3 g, 44%): ¹H NMR (400 MHz, DMSO-d₆) δ7.54-7.58 (m, 1H), 7.45-7.49 (m, 1H), 7.12-7.17 (m, 1H), 4.86 (dd,J=6.8, 4.4 Hz, 1H), 3.27 (t, J=7.2 Hz, 2H), 1.73-1.86 (m, 2H).

Step 3: Coupling ofN-(3-(3-bromo-2-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamideand 1-vinylcyclohexanol gave(E)-2,2,2-trifluoro-N-(3-(2-fluoro-3-(2-(1-hydroxycyclohexyl)vinyl)phenyl)-3-hydroxypropyl)acetamideas a colorless oil. Yield (0.13 g, 54%): ¹H NMR (400 MHz, CD₃OD) δ 7.42(td, J=7.6, 1.2 Hz, 1H), 7.36 (td, J=7.2, 1.2 Hz, 1H), 7.11 (t, J=8.0Hz, 1H), 6.76 (d, J=16 Hz, 1H), 6.42 (d, J=16 Hz, 1H), 5.02 (dd, J=6.8,4.4 Hz, 1H), 3.41 (t, J=7.2 Hz, 2H), 1.73-2.00 (m, 2H), 1.50-1.78 (m,9H), 1.30-1.40 (m, 1H).

Step 4: Deprotection of(E)-2,2,2-trifluoro-N-(3-(2-fluoro-3-(2-(1-hydroxycyclohexyl)vinyl)phenyl)-3-hydroxypropyl)acetamidegave (E)-1-(3-(3-amino-1-hydroxypropyl)-2-fluorostyryl)cyclohexanol as acolorless oil. Yield (0.05 g, 56¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (t,J=6.8 Hz, 1H), 7.29 (t, J=6.4 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 6.62 (d,J=16 Hz, 1H), 6.42 (d, J=16 Hz, 1H), 4.88 (t, J=6.0 Hz, 1H), 2.57 (t,J=7.2 Hz, 2H), 1.10-1.68 (m, 12H).

Step 5: Hydrogenation of(E)-1-(3-(3-amino-1-hydroxypropyl)-2-fluorostyryl)cyclohexanol gaveExample 155 hydrochloride as a while solid. Yield (0.045 g, 85%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.88 (br.s, 3H), 7.06-7.30 (m, 3H), 5.5 (br.s, 1H),4.89-4.92 (m, 2H), 2.78-2.88 (m, 2H), 2.59-2.63 (m, 2H), 1.76-1.96 (m,2H), 1.12-1.62 (m, 13H).

Example 156 Preparation of3-(3-(cyclohexylthiomethyl)phenyl)prop-2-yn-1-amine

3-(3-(Cyclohexylthiomethyl)phenyl)prop-2-yn-1-amine was preparedfollowing the method below.

Step 1. A mixture of cyclohexylmercaptan (1.09 mL, 8.89 mmol),3-bromobenzyl bromide (2.22 g, 8.882 mmol) and K₂CO₃ (2.54 g, 18.38mmol) in acetone was stirred under argon at room temperature for 4 hrsthen filtered. The filtrate was concentrated under reduced pressure.Purification by flash chromatography (0% to 20% EtOAc—hexanes gradient)gave (3-bromobenzyl)(cyclohexyl)sulfane as a colorless oil. Yield (2.02g, 80%); ¹H NMR (400 MHz, CDCl₃) δ 7.48 (t, J=1.8 Hz, 1H), 7.33-7.37 (m,1H), 7.22-7.26 (m, 1H), 7.16 (t, J=7.8 Hz, 1H), 3.68 (s, 2H), tt,J=3.33, 10.0 Hz, 1H), 1.87-1.96 (m, 2H), 1.69-1.77 (m, 2H), 1.53-1.61(m, 1H), 1.18-1.38 (m, 5H).

Step 2. Sonogashira coupling between (3-bromobenzyl)(cyclohexyl)sulfaneand 2,2,2-trifluoro-N-(prop-2-ynyl)acetamide following the method usedin Example 139 gaveN-(3-(3-(cyclohexylthiomethyl)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamideas a yellow oil. Yield (0.70 g, 35%); ¹H NMR (400 MHz, DMSO-d₆) δ 10.0(br t, 1H), 7.24-7.37 (m, 4H), 4.25 (d, J=5.5 Hz, 2H), 3.72 (s, 2H),2.48-2.53 (m, 1H), 1.79-1.87 (m, 2H), 1.58-1.65 (m, 2H), 1.45-1.52 (m,1H), 1.12-1.27 (m, 5H).

Step 3. Deprotection ofN-(3-(3-(cyclohexylthiomethyl)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 138 followed by flashchromatography purification (50% to 100% of 10% 7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) gave Example 156 as a light yellow oil. Yield (0.157 g,85%); ¹H NMR (400 MHz, CD₃OD) δ 7.35-7.37 (m, 1H), 7.20-7.29 (m, 3H),3.70 (s, 2H), 3.58 (s, 2H), 2.46-2.54 (m, 1H), 1.86-1.92 (m, 2H),1.67-1.75 (m, 2H), 1.53-1.60 (m, 1H), 1.20-1.34 (m, 5H); RP-HPLC (Method2): 94.7% (AUC), t_(R)=7.08 min.

Example 157 Preparation of3-(3-(cyclohexylsulfonylmethyl)phenyl)prop-2-yn-1-amine

3-(3-(Cyclohexylsulfonylmethyl)phenyl)prop-2-yn-1-amine was preparedfollowing the method used in Example 135.

Step 1. Oxidation ofN-(3-(3-(cyclohexylthiomethyl)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 135 followed by flashchromatography purification (20% to 70% EtOAc—hexanes gradient) gaveN-(3-(3-(cyclohexylsulfonylmethyl)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamideas a white solid. Yield (0.256 g, 86%); ¹H NMR (400 MHz, DMSO-d₆) δ10.06 (br. t, J=5.1 Hz, 1H), 7.35-7.45 (m, 4H), 4.42 (s, 2H), 4.26 (d,J=5.5 Hz, 2H), 2.94 (tt, J=3.3, 15.3 Hz, 1H), 2.02-2.08 (m, 2H),1.74-1.82 (m, 2H), 1.56-1.63 (m, 1H), 1.30-1.42 (m, 2H), 1.07-1.30 (m,3H).

Step 2. Deprotection ofN-(3-(3-(cyclohexylsulfonylmethyl)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 138 followed by flashchromatography purification (10% to 100% of 10% 7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) gave Example 157 as a white solid. Yield (0.166 g,91%); ¹H NMR (400 MHz, CD₃OD) δ 7.45-7.48 (m, 1H), 7.40 (dt, J=1.8, 7.2Hz, 1H), 7.37 (dt, J=1.8, 7.6 Hz, 1H), 7.33 (t, J=7.4 Hz, 1H), 4.33 (s,2H), 3.59 (s, 2H), 2.93 (tt, J=3.3, 11.9 Hz, 1H), 2.10-2.20 (m, 2H),1.85-1.93 (m, 2H), 1.66-1.73 (m, 1H), 1.45-1.57 (m, 2H), 1.16-1.37 (m,3H); RP-HPLC (Method 2): 99.7% (AUC), t_(R)=5.56 min.

Example 158 Preparation of3-(3-(cyclohexylthiomethyl)phenyl)propan-1-amine

3-(3-(Cyclohexylthiomethyl)phenyl)propan-1-amine was prepared followingthe method used in Example 135.

Step 1. Hydrogenation of Example 157 following the method used inExample 2 followed by flash chromatography purification (10% to 100% 10%7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) gave Example 158 as a colorless oil.Yield (0.0844 g, 91%); ¹H NMR (400 MHz, CD₃OD) δ 7.14-7.20 (m, 2H),7.09-7.13 (m, 1H), 7.01-7.07 (m, 1H), 3.70 (s, 2H), 2.58-2.66 (m, 4H),2.45-2.57 (m, 1H), 1.86-1.94 (m, 2H), 1.67-1.80 (m, 4H), 1.54-1.60 (m,1H), 1.20-1.33 (m, 5H); RP-HPLC (Method 2): 92.8% (AUC), t_(R)=7.09 min;LC-MS (ESI+) 264.221 [M+H]⁺.

Example 159 Preparation of3-(3-(cyclohexylsulfonylmethyl)phenyl)propan-1-amine

3-(3-(Cyclohexylsulfonylmethyl)phenyl)propan-1-amine was preparedfollowing the method below.

Step 1. Hydrogenation ofN-(3-(3-(cyclohexylthiomethyl)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 2 followed by flash chromatographypurification (5% to 20% EtOAc—hexanes gradient) gaveN-(3-(3-(cyclohexylthiomethyl)phenyl)propyl)-2,2,2-trifluoroacetamide asa colorless oil. Yield (0.121 g, 72%); ¹H NMR (400 MHz, CDCl₃) δ7.20-7.26 (m, 1H), 7.12-7.17 (m, 2H), 7.01-7.06 (m, 1H), 6.17 (br.s,1H), 3.71 (s, 2H), 3.38 (q, J=6.9 Hz, 2H), 2.66 (t, J=7.4 Hz, 2H), 2.56(tt, J=3.5, 10.4 Hz, 1H), 1.87-1.97 (m, 4H), 1.68-1.77 (m, 2H),1.54-1.61 (m, 1H), 1.19-1.38 (m, 5H).

Step 2. Oxidation ofN-(3-(3-(cyclohexylthiomethyl)phenyl)propyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 135 followed by flashchromatography purification (10% to 40% EtOAc—hexanes gradient) gaveN-(3-(3-(cyclohexylsulfonylmethyl)phenyl)propyl)-2,2,2-trifluoroacetamideas a colorless oil, which solidified to white solid. Yield (0.112 g,85%); ¹H NMR (400 MHz, CDCl₃) δ 7.32 (t, J=7.4 Hz, 1H), 7.17-7.26 (m,3H), 6.37 (br.s, 1H), 4.15 (s, 2H), 3.33 (q, J=6.7 Hz, 2H), 2.76 (tt,J=3.5, 12.1 Hz, 1H), 2.69 (t, J=7.6 Hz, 2H), 2.10-2.18 (m, 2H),1.87-1.97 (m, 4H), 1.66-1.73 (m, 1H), 1.51-1.63 (m, 2H), 1.18-1.30 (m,3H).

Deprotection ofN-(3-(3-(cyclohexylsulfonylmethyl)phenyl)propyl)-2,2,2-trifluoroacetamidefollowing the method used in Example 138 followed by flashchromatography purification (10% to 100% of 10% 7N NH₃/MeOH/CH₂Cl₂—CH₂Cl₂ gradient) gave Example 159 as a white solid. Yield (0.062 g,73%); ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.318 (m, 4H), 4.31 (s, 2H), 2.91(tt, J=3.5, 11.9 Hz, 1H), 2.61-2.69 (m, 4H), 2.10-2.18 (m, 2H),1.85-1.93 (m, 2H), 1.73-1.81 (m, 2H), 1.66-1.73 (m, 1H), 1.44-1.56 (m,2H), 1.17-1.36 (m, 3H); ¹³C NMR (100 MHz, CD₃OD) δ 142.8, 131.1, 128.65,128.54, 128.50, 128.08, 59.8, 55.5, 40.8, 34.3, 32.8, 25.2, 25.0, 24.9;RP-HPLC (Method 2): 96.8% (AUC), t_(R)=5.60 min; LC-MS (ESI+) 296.55[M+H]⁺.

Example 160 Preparation of(E)-3-(3-(cyclohexyloxymethyl)phenyl)prop-2-en-1-amine

(E)-3-(3-(Cyclohexyloxymethyl)phenyl)prop-2-en-1-amine was preparedfollowing the method used in Examples 2, 9 and 118.

Step 1: Reaction of 1-bromo-3-(bromomethyl)benzene with cyclohexylaminefollowing the method described in Example 9 except cesium carbonate wasused as base and at 90° C. for 18 h gaveN-(3-bromobenzyl)cyclohexylamine as a white solid. Yield (0.70 g, 65%):¹H NMR (400 MHz, CD₃OD) δ 7.53 (t, J=1.6 Hz, 1H), 7.38-7.41 (m, 1H),7.29 (d, J=7.6 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 3.73 (s, 2H), 2.38-2.46(m, 1H), 1.92-1.95 (m, 2H), 1.70-1.78 (m, 2H), 1.58-1.66 (m, 1H),1.06-1.30 (m, 5H).

Step 2: Heck coupling of N-(3-bromobenzyl)cyclohexanamine andN-allyl-2,2,2-trifluoroacetamide following the method described inExample 118 gave(E)-N-(3-(3-((cyclohexylamino)methyl)phenyl)allyl)-2,2,2-trifluoroacetamideas a colorless oil. Yield (0.20 g, 22%): ¹H NMR (400 MHz, CD₃OD) δ 7.55(s, 1H), 7.48-7.50 (m, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.35-7.37 (m, 1H),6.61 (d, J=16.0 Hz, 1H), 6.32 (dt, J=16.0, 6.4 Hz, 1H), 4.19 (s, 2H),4.05 (d, J=6.4 Hz, 2H), 3.07-3.16 (m, 1H), 2.14-2.22 (m, 2H), 1.66-1.82(m, 2H), 1.68-1.76 (m, 1H), 1.16-1.50 (m, 5H).

Step 3: Deprotection of(E)-N-(3-(3-((cyclohexylamino)methyl)phenyl)allyl)-2,2,2-trifluoroacetamidefollowing method described in Example 2 gave Example 160 as a whitesolid. Yield (0.04 g, 23%): ¹H NMR (400 MHz, CD₃OD) δ 7.69 (s, 1H),7.53-7.56 (m, 1H), 7.42-7.48 (m, 2H), 6.84 (d, J=16.0 Hz, 1H), 6.40 (dt,J=16.0, 6.8 Hz, 1H), 4.23 (s, 2H), 4.73 (d, J=6.4 Hz, 2H), 3.08-3.16 (m,1H), 2.16-2.24 (m, 2H), 1.86-1.94 (m, 2H), 1.68-1.76 (m, 1H), 1.30-1.50(m, 5H).

Example 161 Preparation of 4-(3-(aminomethyl)phenethyl)heptan-4-ol

4-(3-(Aminomethyl)phenethyl)heptan-4-ol was prepared following themethod below.

Step 1: N-(3-Bromobenzyl)-2,2,2-trifluoroacetamide was coupled with4-ethynylheptan-4-ol following the procedure described in Example 140 togive 2,2,2-trifluoro-N-(3-(3-hydroxy-3-propylhex-1-ynyl)benzyl)acetamideas a yellow oil. Yield (0.462 g, 38%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.97(t, J=5.6 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.27-7.22 (m, 3H), 5.15 (bs,1H), 4.35 (d, J=6.0 Hz, 2H), 1.60-1.41 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).

Step 2:2,2,2-Trifluoro-N-(3-(3-hydroxy-3-propylhex-1-ynyl)benzyl)acetamide wasdeprotected following the procedure in Example 140 to give4-((3-(aminomethyl)phenyl)ethynyl)heptan-4-ol as a pale yellow oil.Yield (0.254 g, 78%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.33 (s, 1H),7.27-7.22 (m, 2H), 7.18-7.16 (m, 1H), 5.11 (bs, 1H), 3.66 (s, 2H), 1.97(bs, 2H), 1.60-1.42 (m, 8H), 0.89 (t, J=7.0 Hz, 6H).

Step 3. Hydrogenation of 4-((3-(aminomethyl)phenyl)ethynyl)heptan-4-olgave Example 161 as a pale yellow oil. Yield (0.10 g, 100%): ¹H NMR (400MHz, DMSO-d₆) δ 7.15 (t, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J=8.0 Hz,1H), 6.97 (d, J=7.2 Hz, 1H), 3.94 (bs, 1H), 3.64 (s, 2H), 2.51-2.47 (m,obs., 2H), 1.92 (bs, 2H), 1.35-1.21 (m, 8H), 0.85 (t, J=7.0 Hz, 6H).

Example 162 Preparation of 4-(3-(2-aminoethyl)phenethyl)heptan-4-ol

4-(3-(2-Aminoethyl)phenethyl)heptan-4-ol was prepared following themethod used in Example 161.

Step 1. Coupling of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide with4-ethynylheptan-4-ol gave2,2,2-trifluoro-N-(3-(3-hydroxy-3-propylhex-1-ynyl)phenethyl)acetamideas a yellow oil. Yield (0.902 g, 65%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.43(t, J=5.2 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.20-7.15 (m, 3H), 5.11 (s,1H), 3.41-3.36 (m, 2H), 2.76 (t, J=7.0 Hz, 2H), 1.61-1.40 (m, 8H), 0.89(t, J=7.2 Hz, 6H).

Step 2.2,2,2-Trifluoro-N-(3-(3-hydroxy-3-propylhex-1-ynyl)phenethyl)acetamidewas deprotected to give 4-((3-(2-aminoethyl)phenyl)ethynyl)heptan-4-olas a pale yellow oil. Yield (0.504 g, 78%): ¹H NMR (400 MHz, DMSO-d₆) δ7.25-7.21 (m, 1H), 7.17-7.14 (m, 3H), 5.12 (bs, 1H), 2.74-2.70 (m, 2H),2.58 (t, J=7.2 Hz, 2H), 1.60-1.41 (m, 8H), 1.34 (bs, 2H), 0.89 (t, J=7.2Hz, 6H).

Step 3. Hydrogenation of 4-((3-(2-aminoethyl)phenyl)ethynyl)heptan-4-olgave Example 162 as a pale yellow oil. Yield (0.11 g, 100%): ¹H NMR (400MHz, DMSO-d₆) δ 7.13 (t, J=7.6 Hz, 1H), 6.96-6.94 (m, 3H), 3.93 (bs,1H), 2.73-2.69 (m, 2H), 2.56 (t, J=7.4 Hz, 2H), 2.50-2.46 (m, obs., 2H),1.55-1.51 (m, 2H), 1.34-1.20 (m, 8H), 0.84 (t, J=7.0 Hz, 6H).

Example 163 Preparation of 3-(3-aminopropyl)-o-cyclohexylbenzamide

3-(3-Aminopropyl)-o-cyclohexylbenzamide was prepared following themethod used in Examples 2, 19 and 118.

Step 1: A solution of 3-bromobenzoyl chloride (2.0 g, 9.1 mmol) inCH₂Cl₂ was added to a solution triethylamine (1.9 ml, 13.7 mmol) andcyclohexylamine (1.15 ml, 10.0 mmol) in CH₂Cl₂ at room temperature withstirring. After 2 h, the mixture was washed with HCl (4N), brine, driedover Na₂SO₄ and concentrated under reduced pressure to give3-bromo-N-cyclohexylbenzamide as a white solid. Yield (2.43 g, 95%): ¹HNMR (400 MHz, CD₃OD) δ 8.29 (br s, 1H), 7.95 (t, J=2.0 Hz, 1H),7.42-7.77 (m, 1H), 7.64-7.67 (m, 1H), 7.36 (t, J=8.0 Hz, 1H), 3.78-3.84(m, 1H), 1.92-1.94 (m, 2H), 1.78-1.81 (m, 2H), 1.65-1.69 (m, 1H),1.16-1.46 (m, 5H).

Step 2: Heck coupling of 3-bromo-N-cyclohexylbenzamide andN-allyl-2,2,2-trifluoroacetamide following the method described inExample 118 gave(E)-N-cyclohexyl-3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)benzamide asa light yellow solid. Yield (0.50 g, 71%): ¹H NMR (400 MHz, CD₃OD) δ8.18-8.26 (m, 1H), 7.83 (t, J=1.6 Hz, 1H), 7.65-7.68 (m, 1H), 7.54-7.56(m, 1H), 7.39 (t, J=7.6 Hz, 1H), 6.62 (d, J=16.0 Hz, 1H), 6.32 (dt,J=16.0, 6.4 Hz, 1H), 4.06 (d, J=5.6 Hz, 2H), 3.80-3.90 (m, 1H),1.93-1.95 (m, 2H), 1.79-1.82 (m, 2H), 1.66-1.70 (m, 1H), 1.18-1.48 (m,5H).

Step 3: Hydrogenation of(E)-N-cyclohexyl-3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)benzamidefollowing method described in Example 154 gaveN-cyclohexyl-3-(3-(2,2,2-trifluoroacetamido)propyl)benzamide as a whitesolid. Yield (0.35 g, 87¹H NMR (400 MHz, CD₃OD) δ 8.08-8.14 (m, 1H),7.58-7.64 (m, 2H), 7.34-7.38 (m, 2H), 7.39 (t, J=7.6 Hz, 1H), 3.80-3.90(m, 1H), 2.70 (t, J=8.0 Hz, 2H), 1.86-1.95 (m, 4H), 1.79-1.82 (m, 2H),1.66-1.70 (m, 1H), 1.16-1.42 (m, 5H).

Step 4: Deprotection ofN-cyclohexyl-3-(3-(2,2,2-trifluoroacetamido)propyl)benzamide followingmethod described in Example 154 gave Example 163 hydrochloride as awhite solid. Yield (0.07 g, 25%): ¹H NMR (400 MHz, CD₃OD) δ 7.58-7.66(m, 2H), 7.30-7.38 (m, 2H), 3.78-3.88 (m, 1H), 2.65-2.80 (m, 4H),1.75-1.95 (m, 6H), 1.66-1.69 (m, 1H), 1.15-1.45 (m, 5H).

Example 164 Preparation of 3-(2-aminoethoxy)-n-cyclohexylbenzamide

3-(2-Aminoethoxy)-N-cyclohexylbenzamide was prepared following themethod used in Examples 9 and 13.

Step 1: Coupling of methyl 3-hydroxybenzoate with2-(tert-butoxycarbonylamino)ethyl methanesulfonate following the methodused in Example 9 gave methyl3-(2-(tert-butoxycarbonylamino)ethoxy)benzoate as a light yellow oil.Yield (0.65 g, 84%): ¹H NMR (400 MHz, CD₃OD) δ 7.36 (t, J=8.0 Hz, 1H),7.26 (t, J=8.0 Hz, 1H), 7.16 (ddd, J=8.4, 2.4, 0.8 Hz, 1H), 6.99 (ddd,J=8.0, 2.4, 0.8 Hz, 1H), 4.03 (t, J=5.6 Hz, 2H), 3.78 (s, 3H), 1.43 (s,9H).

Step 2: Hydrolysis of methyl3-(2-(tert-butoxycarbonylamino)ethoxy)benzoate following the method usedin Example 9 except that LiOH and THF were used instead of K₂CO₃ andMeOH gave 3-(2-(tert-butoxycarbonylamino)ethoxy)benzoic acid that wasused directly in next reaction without further purification.

Step 3: To a solution of 3-(2-(tert-butoxycarbonylamino)ethoxy)benzoicacid (0.73 g, 2.98 mmol), cyclohexylamine (0.34 ml, 2.98 mmol), EDCI(0.7 g, 3.58 mmol) and HOBT (0.49 g, 3.58 mmol) in DMF was added DIPEA(1.0 ml, 5.57 mmol). The resulting mixture was stirred at roomtemperature for 18 h, concentrated, and partitioned between ethylacetate and water. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by flashchromatography (30 to 65% EtOAc-hexanes gradient) gave tert-butyl2-(3-(cyclohexylcarbamoyl)phenoxy)ethylcarbamate as an orange oil. Yield(0.20 g, 20%): ¹H NMR (400 MHz, CD₃OD) δ 7.31-7.38 (m, 3H), 7.06-7.09(m, 1H), 4.04 (t, J=5.6 Hz, 2H), 3.78-3.87 (m, 1H), 3.41-3.45 (m, 2H),1.90-1.98 (m, 2H), 1.78-1.84 (m, 2H), 1.63-1.71 (m, 1H), 1.43 (s, 9H),1.18-1.38 (m, 5H).

Step 4: Deprotection of tert-butyl2-(3-(cyclohexylcarbamoyl)phenoxy)ethylcarbamate following methoddescribed in Example 151 gave Example 164 hydrochloride as a whitesolid. Yield (0.11 g, 60%): ¹H NMR (400 MHz, CD₃OD) δ 7.36-7.44 (m, 3H),7.14-7.17 (m, 1H), 4.27 (t, J=5.2 Hz, 2H), 3.80-3.90 (m, 1H), 3.37 (t,J⁼5.2 Hz, 2H), 1.92-1.98 (m, 2H), 1.78-1.86 (m, 2H), 1.65-1.72 (m, 1H),1.15-1.48 (m, 5H).

Example 165 Preparation of 3-(3-aminopropyl)-N-(heptan-4-yl)benzamide

3-(3-Aminopropyl)-N-(heptan-4-yl)benzamide was prepared following themethod used in Example 163:

Step 1: Reaction of 3-bromobenzoyl chloride with heptan-4-amine gave3-bromo-N-(heptan-4-yl)benzamide as a white solid which was used in thenext step without additional purification. Yield (2.43 g, 90%).

Step 2: Coupling of 3-bromo-N-(heptan-4-yl)benzamide andN-allyl-2,2,2-trifluoroacetamide gave(E)-N-(heptan-4-yl)-3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)benzamideas a light yellow solid. Yield (0.65 g, 80%): ¹H NMR (400 MHz, CD₃OD) δ8.09-8.11 (m, 1H), 7.81-7.84 (m, 1H), 7.65-7.68 (m, 1H), 7.54-7.56 (m,1H), 7.40 (t, J=1.6 Hz, 1H), 6.63 (d, J=16.0 Hz, 1H), 6.33 (dt, J=16.0,6.4 Hz, 1H), 4.06 (d, J=6.0 Hz, 2H), 1.50-1.56 (m, 4H), 1.32-1.46 (m,5H), 0.93 (t, J=7.2 Hz, 6H).

Step 3: Hydrogenation of(E)-N-(heptan-4-yl)-3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)benzamidegave N-(heptan-4-yl)-3-(3-(2,2,2-trifluoroacetamido)propyl)benzamide asa white solid. Yield (0.30 g, 99%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.43 (t,J=5.6 Hz, 1H), 7.92 (d, J=8.80 Hz, 1H), 7.60-7.66 (m, 2H), 7.30-7.36 (m,2H), 3.90-4.0 (m, 1H), 3.16-3.22 (m, 2H), 2.61 (t, J=8.4 Hz, 2H),1.76-1.83 (m, 1H), 1.20-1.48 (m, 8H), 0.84 (t, J=7.2 Hz, 6H).

Step 4: Deprotection ofN-(heptan-4-yl)-3-(3-(2,2,2-trifluoroacetamido)propyl)benzamide gaveExample 165 hydrochloride as a white solid. Yield (0.18 g, 67%): ¹H NMR(400 MHz, CD₃OD) δ 7.62-7.68 (m, 2H), 7.30-7.40 (m, 2H), 4.05-4.12 (m,1H), 2.93 (t, J=8.0 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 1.95-2.05 (m, 2H),1.50-1.56 (m, 4H), 1.30-1.46 (m, 4H), 0.93 (t, J=7.6 Hz, 6H).

Example 166 Preparation of3-(3-aminopropyl)-N-(2,6-dimethylphenyl)benzamide

3-(3-Aminopropyl)-N-(2,6-dimethylphenyl)benzamide was prepared followingthe method shown in Scheme 33.

Step 1: To a solution of 2,6-dimethyl aniline (0.5 mL, 4.0 mmol) and3-iodobenzoic acid (1.0 g, 4.0 mmol) in anhydrous pyridine was addedBOP-Cl (2.05 g, 8 mmol). The reaction mixture was stirred at roomtemperature for two hrs, then extracted from 1N HCl with ethyl acetate.The combined organic layers were washed with HCl (1N), water, and brine,dried over Na₂SO₄, filtered, and concentrated under reduced vacuum.Purification by flash chromatography (10-20% ethyl acetate/hexanesgradient) gave amide 166 as a white solid. Yield (0.35 g, 25%): ¹H NMR(400 MHz, DMSO-d6) δ 8.3 (s, 1H), 7.87-7.92 (m, 2H), 7.10-7.29 (m, 5H),2.30 (s, 6H).

Step 2: Sonogashira coupling of iodide 166 with tert-butylprop-2-ynylcarbamate following the method used in Example 2, except thattriphenylphosphine was used instead of tri-tolyl-o-phosphine, followedby flash chromatography (15-40% ethyl acetate/hexanes gradient), gavethe alkyne 167 as a light yellow solid. Yield (0.321 g, 83%): ¹H NMR(400 MHz, DMSO-d₆) δ 7.96-7.99 (m, 1H), 7.88-7.92 (m, 1H), 7.60-7.65 (m,1H), 7.48 (t, J=8.0 Hz, 1H), 7.33 (brs, 1H), 7.13-7.21 (m, 3H), 4.58(brs, 1H), 4.10-4.30 (m, 2H), 2.31 (s, 6H), 1.50 (s, 9H).

Step 3: Hydrogenation of alkyne 167 following the method used in Example2, followed by flash chromatography (10-35% EtOAc/hexanes gradient) gavealkane 168 as a colorless oil. Yield (0.083 g, 69%): ¹H NMR (400 MHz,DMSO-d6) δ 8.01 (br.s, 1H), 7.78-7.86 (m, 2H), 7.37-7.47 (m, 2H),7.10-7.28 (m, 3H), 4.65 (brs, 1H), 3.16-3.23 (m, 2H), 2.76 (t, J=8.0 Hz,2H), 2.31 (s, 6H), 1.87 (quint, J=8.0 Hz, 2H), 1.38 (s, 9H).

Step 4: Deprotection of carbamate 168 following the method used inExample 34 gave Example 166 hydrochloride as a light tan solid. Yield(0.018 g, 43%): ¹H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.85-8.0 (m,5H), 7.42-7.50 (m, 2H), 7.13 (s, 3H), 2.78-2.87 (m, 2H), 2.75 (t, J=8.0Hz, 2H), 2.19 (s, 6H), 1.91 (quint, J=8.0 Hz, 2H). ESI MS m/z 283.3[m+H]⁺

Example 167 Preparation of4-(3-(1-hydroxy-3-(methylamino)propyl)phenethyl)heptan-4-ol

4-(3-(1-Hydroxy-3-(methylamino)propyl)phenethyl)heptan-4-ol is preparedfollowing the method used in Example 17 and in Scheme 34.

Step 1: Protection of4-(3-(3-amino-1-hydroxypropyl)phenethyl)heptan-4-ol using (Boc)₂Ofollowing the method described in Example 17 gives tert-butyl3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate.

Step 2: Reduction of tert-butyl3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate usingBH₃-THF gives Example 167.

Example 168 Preparation of1-(3-(3-hydroxy-3-propylhexyl)benzyl)guanidine

1-(3-(3-Hydroxy-3-propylhexyl)benzyl)guanidine is prepared following themethod described in Scheme 35.

Step 1: Coupling of 4-ethynylheptan-4-ol with 3-bromobenzonitrilefollowing the method described in Example 12 gives3-(3-hydroxy-3-propylhex-1-ynyl)benzonitrile.

Step 2: Hydrogenation of 3-(3-hydroxy-3-propylhex-1-ynyl)benzonitrilefollowing the method described in Example 12 gives3-(3-hydroxy-3-propylhexyl)benzonitrile

Step 3: Reduction of 3-(3-hydroxy-3-propylhexyl)benzonitrile followingthe method described in Example 15 gives4-(3-(aminomethyl)phenethyl)heptan-4-ol.

Step 4: Reaction of 4-(3-(aminomethyl)phenethyl)heptan-4-ol withtert-butyl (1H-pyrazol-1-yl)methylenedicarbamate in CH₃CN givestert-butyl(tert-butoxycarbonylamino)(3-(3-hydroxy-3-propylhexyl)benzylamino)methylenecarbamate.

Step 5: Deprotection of tert-butyl(tert-butoxycarbonylamino)(3-(3-hydroxy-3-propylhexyl)benzylamino)methylenecarbamatefollowing the method used in Example 13 gives Example 168.

Example 169 Preparation of1-(3-(3-(3-hydroxy-3-propylhexyl)phenyl)propyl)guanidine

1-(3-(3-(3-Hydroxy-3-propylhexyl)phenyl)propyl)guanidine is preparedfollowing the method used in Examples 12, 118 and 168 in Scheme 35.

Step 1: Hydrogenation of(E)-4-(3-(3-aminoprop-1-enyl)phenethyl)heptan-4-ol following the methoddescribed in Example 12 gives 4-(3-(3-aminopropyl)phenethyl)heptan-4-ol.

Step 2: Reaction of 4-(3-(3-aminopropyl)phenethyl)heptan-4-ol withtert-butyl (1H-pyrazol-1-yl)methylenedicarbamate following the methoddescribed in Example 168 gives tert-butyl(tert-butoxycarbonylamino)(3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylamino)methylenecarbamate.

Step 3: Deprotection of tert-butyl(tert-butoxycarbonylamino)(3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylamino)methylenecarbamatefollowing the method used in Example 13 gives Example 169.

Example 170 Preparation of3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propanimidamide

3-Hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propanimidamide isprepared following the method described in Scheme 36.

Step 1: Coupling of 4-ethynylheptan-4-ol with3-(3-bromophenyl)-3-hydroxypropanenitrile following the method describedin Example 12 gives3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propanenitrile as alight yellow oil.

Step 2: Hydrogenation of3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propanenitrilefollowing the method described in Example 12 gives3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propanenitrile.

Step 3: Into an ice cold solution of3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl) in absolute EtOH isbubbled HCl gas for 4 to 5 min. This mixture is allowed to warm to roomtemperature and stirred. The solvent is removed under reduced pressure.To the residue is added absolute EtOH with cooling in an ice bath andNH₃ gas is bubbled into the solution for 2-3 min. The mixture is allowedto warm to room temperature and stirred for 4 h. The mixture isconcentrated under reduced pressure. To the residue is added absoluteEtOH with cooling in an ice bath. HCl gas is bubbled into the solutionfor 1 min. and the mixture is concentrated under reduced pressure. Theresidue is dissolved in H₂O and extracted with EtOAc. The aqueous layeris evaporated to dryness and dried under high vacuum overnight to giveExample 170.

Example 171 Preparation of1-amino-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propan-2-one

1-Amino-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propan-2-one is preparedfollowing the method used in Example 19.

Step 1: Protection of4-(3-(3-amino-2-hydroxypropyl)phenethyl)heptan-4-ol (Example 143) using(Boc)₂O following the method described in Example 17 gives tert-butyl2-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate.

Step 2: Oxidation of tert-butyl2-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate followingthe method used in Example 151 gives tert-butyl3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-oxopropylcarbamate.

Step 3: Deprotection of tert-butyl3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-oxopropylcarbamate following themethod used in Example 13 gives Example 171 hydrochloride salt.

Example 172 Preparation of4-(3-(3-amino-2-fluoropropyl)phenethyl)heptan-4-ol

4-(3-(3-Amino-2-fluoropropyl)phenethyl)heptan-4-ol is prepared followingthe method used in Example 174 except Example 143 is used instead ofalcohol 39.

Example 173 Preparation of3-amino-1-(3-(3-hydroxy-3-propylhexyl)phenyl)propan-1-one

3-Amino-1-(3-(3-hydroxy-3-propylhexyl)phenyl)propan-1-one is preparedfollowing the method used in Example 19.

Step 1: Protection of4-(3-(3-amino-1-hydroxypropyl)phenethyl)heptan-4-ol using (Boc)₂Ofollowing the method described in Example 17 gives tert-butyl3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate.

Step 2: Oxidation of tert-butyl3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate followingthe method used in Example 151 gives tert-butyl3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate.

Step 3: Deprotection of tert-butyl3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate followingthe method used in Example 13 gives Example 173 hydrochloride salt.

Example 174 Preparation of4-(3-(3-amino-1-fluoropropyl)phenethyl)heptan-4-ol

4-(3-(3-Amino-1-fluoropropyl)phenethyl)heptan-4-ol is prepared followingthe method below.

Step 1: Diethylaminosulphur trifluoride (DAST) is added under an inertatmosphere to a cold (−78° C.) solution of alcohol 39. The reactionmixture is stirred at −78° C. until no starting material is seen by TLC.The reaction mixture is partitioned between water and EtOAc, and aqueouslayer is extracted with EtOAc. The combined organic layers are washedwith brine and dried over anhydrous MgSO₄. Purification by flashchromatography gives tert-butyl3-(3-bromophenyl)-3-fluoropropylcarbamate.

Step 2: Sonogashira coupling of tert-butyl3-(3-bromophenyl)-3-fluoropropylcarbamate and 4-ethynylheptan-4-olfollowing the method described in Example 12 gives tert-butyl3-fluoro-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propylcarbamate.

Step 3: Hydrogenation of tert-butyl3-fluoro-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propylcarbamatefollowing the method used in Example 12 gives tert-butyl3-fluoro-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate.

Step 4. Deprotection of tert-butyl3-fluoro-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate followingthe method used in Example 13 gives Example 174.

Example 175 Preparation of 4-(3-(4-aminobutan-2-yl)phenethyl)heptan-4-ol

4-(3-(4-Aminobutan-2-yl)phenethyl)heptan-4-ol is prepared following themethod used in Scheme 37.

Step 1: To a suspension of methyltriphenylphosponium bromide in THF isadded KOBu-t (1 M in THF, 6.1 mmol) at room temperature. After stirringfor 30 mins, tert-butyl3-(3-(3-hydroxy-3-propylhexyl)phenyl)-3-oxopropylcarbamate is added. Theresulting mixture is stirred at room temperature for 18 h. The reactionis quenched by the addition of AcOH. The mixture is filtered andconcentrated under reduced pressure. Purification by flashchromatography (15 to 50% EtOAc-hexanes gradient) gives tert-butyl3-(3-(3-hydroxy-3-propylhexyl)phenyl)but-3-enylcarbamate.

Step 2: Hydrogenation of tert-butyl3-(3-(3-hydroxy-3-propylhexyl)phenyl)but-3-enylcarbamate following themethod described in Example 12 gives tert-butyl3-(3-(3-hydroxy-3-propylhexyl)phenyl)butylcarbamate.

Step 3: Deprotection of tert-butyl3-(3-(3-hydroxy-3-propylhexyl)phenyl)butylcarbamate following the methodused in Example 13 gives Example 175 hydrochloride salt.

Example 176 Preparation of4-(3-(3-amino-1-hydroxypropyl)-5-chlorophenethyl)heptan-4-ol

4-(3-(3-Amino-1-hydroxypropyl)-5-chlorophenethyl)heptan-4-ol is preparedfollowing the methods used in Examples 16, 17 and 19 except3-bromo-5-chlorobenzaldehyde is used instead of 3-bromobenzaldehyde.

Example 177 Preparation of(R)-3-(3-amino-1-hydroxypropyl)-n-(heptan-4-yl)benzamide

(R)-3-(3-amino-1-hydroxypropyl)-N-(heptan-4-yl)benzamide is preparedfollowing the methods used in Examples 71 and 163 using 3-formylbenzoicacid as starting material.

Example 178 Preparation of 4-(3-(3-aminobutyl)phenethyl)heptan-4-ol

4-(3-(3-Aminobutyl)phenethyl)heptan-4-ol is prepared following themethod used Examples 12 and 180 using vinyl methyl ketone in place ofallyl trifluoroacetamide.

Example 179 Preparation of(R)-3-(3-amino-1-hydroxypropyl)-n-cyclohexyl-n-methylbenzamide

(R)-3-(3-Amino-1-hydroxypropyl)-N-cyclohexyl-N-methylbenzamide isprepared following the method used in Example 177.

Example 180 Preparation of1-(3-((1R,2R)-3-amino-1-hydroxy-2-methylpropyl)phenethyl)cyclopentanol

1-(3-((1R,2R)-3-Amino-1-hydroxy-2-methylpropyl)phenethyl)cyclopentanolis prepared following the method used in Scheme 38.

Step 1: To a mixture of (S)-4-benzyl-3-propionyloxazolidin-2-one,anhydrous MgCl₂ (0.104 g, 1.09 mmol) and 3-bromobenzaldehyde in EtOAc isadded Et₃N followed by chlorotrimethylsilane. The reaction mixture isstirred under argon at room temperature for 24 h and then filteredthrough a layer of a silica gel, washing with EtOAc. The combinedfiltrates are concentrated under reduced pressure and the residue ispurified by flash chromatography (1 to 30% EtOAc/hexane gradient) togive(S)-4-benzyl-3-((2R,3S)-3-(3-bromophenyl)-2-methyl-3-(trimethylsilyloxy)propanoyl)oxazolidin-2-one.

Step 2: To a solution of(S)-4-benzyl-3-((2R,3S)-3-(3-bromophenyl)-2-methyl-3-(trimethylsilyloxy)propanoyl)oxazolidin-2-onein anhydrous THF is added a solution of LiBH₄ in THF under argon. Thereaction mixture is stirred for 18 h at room temperature and a saturatedaqueous solution of NH₄Cl is slowly added followed by MTBE. The mixtureis stirred for 15 mins, layers are separated, organic layer is washedwith brine, dried over anhydrous MgSO₄, filtered and concentrated underreduced pressure. The residue is purified by flash chromatography (5 to40% EtOAc/hexane gradient) to give(2S,3S)-3-(3-bromophenyl)-2-methyl-3-(trimethylsilyloxy)propan-1-ol.

Step 3: To a cold (0° C.) solution of(2S,3S)-3-(3-bromophenyl)-2-methyl-3-(trimethylsilyloxy)propan-1-ol,phthalimide and Ph₃P in anhydrous THF under argon is added solution ofdiethyl azodicarboxylate in anhydrous THF. The reaction mixture isstirred for 1 hour under argon while warming to room temperature andthen the solvent is removed in vacuum, the residue is dissolved indichloromethane/hexane and purified by flash chromatography (5 to 30%EtOAc/hexane gradient) to2-((2S,3S)-3-(3-bromophenyl)-2-methyl-3-(trimethylsilyloxy)propyl)isoindoline-1,3-dione.

Step 4: Coupling of2-((2S,3S)-3-(3-bromophenyl)-2-methyl-3-(trimethylsilyloxy)propyl)isoindoline-1,3-dionewith 4-ethynylheptan-4-ol following the method in Example 12 gives2-((2S,3S)-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-2-methyl-3-(trimethylsilyloxy)propyl)isoindoline-1,3-dione.

Step 5: Hydrogenation of2-((2S,3S)-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-2-methyl-3-(trimethylsilyloxy)propyl)isoindoline-1,3-dionefollowing the method used in Example 12 gives2-((2S,3S)-3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-methyl-3-(trimethylsilyloxy)propyl)isoindoline-1,3-dione.

Step 6: To a solution of2-((2S,3S)-3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-methyl-3-(trimethylsilyloxy)propyl)isoindoline-1,3-dionein EtOH is added trifluoroacetic acid. The reaction mixture is stirredat room temperature then concentrated under reduced pressure,re-evaporated with EtOAc then with hexane to give2-((2S,3S)-3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-methylpropyl)isoindoline-1,3-dione.

Step 7: Phthalimide cleavage of2-((2S,3S)-3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-methylpropyl)isoindoline-1,3-dioneis performed following the method described in Example 9 gives Example180.

Example 181 Preparation of1-(3-(3-aminopropyl)-5-methylphenethyl)cyclohexanol

1-(3-(3-Aminopropyl)-5-methylphenethyl)cyclohexanol is preparedfollowing the method shown in Scheme 39.

Steps 1 to 4: The procedure for the synthesis of(E)-1-(3-(3-aminoprop-1-enyl)-5-methylphenethyl)cyclohexanol is the sameas for the synthesis of Example 183 except1-bromo-3-iodo-5-methylbenzene and 1-ethynylcyclohexanol are usedinstead of 1-bromo-3-iodobenzene and 4-ethynylheptan-4-ol.

Step 5: Hydrogenation of(E)-1-(3-(3-aminoprop-1-enyl)-5-methylphenethyl)cyclohexanol followingthe method described in Example 12 gives Example 181.

Example 182 Preparation of1-(3-(3-aminopropyl)-4-fluorophenethyl)cyclohexanol

1-(3-(3-Aminopropyl)-4-fluorophenethyl)cyclohexanol is preparedfollowing the method used in Example 181.

Steps 1 to 4: The procedure for the synthesis of(E)-1-(3-(3-aminoprop-1-enyl)-4-fluorophenethyl)cyclohexanol is the sameas for the synthesis of Example 181 except2-bromo-1-fluoro-4-iodobenzene is used instead of 1-bromo-3-iodobenzene.

Step 5: Hydrogenation of(E)-1-(3-(3-aminoprop-1-enyl)-4-fluorophenethyl)cyclohexanol followingthe method described in Example 12 gives Example 182.

Example 183 Preparation of(E)-1-(3-(3-aminoprop-1-enyl)phenethyl)cyclohexanol

(E)-1-(3-(3-Aminoprop-1-enyl)phenethyl)cyclohexanol is preparedfollowing the method shown in Scheme 40.

Step 1: Coupling of cyclohexylmethanol with 1-bromo-3-iodobenzenefollowing the method described in Example 12 gives1-((3-bromophenyl)ethynyl)cyclohexanol as a light yellow oil.

Step 2: Hydrogenation 1-((3-bromophenyl)ethynyl)cyclohexanol followingthe method described in Example 12 gives1-(3-bromophenethyl)cyclohexanol.

Step 3: Coupling of 1-(3-bromophenethyl)cyclohexanol withN-allyl-2,2,2-trifluoroacetamide following the method described inExample 118 gives(E)-2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)allyl)acetamide.

Step 4: Deprotection of(E)-2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)allyl)acetamidefollowing the method described in Example 2 gives Example 183.

Example 184 Preparation of1-(3-(3-aminoprop-1-ynyl)phenethyl)cyclohexanol

1-(3-(3-Aminoprop-1-ynyl)phenethyl)cyclohexanol is prepared followingthe method used in Example 12.

Step 1: Coupling of 1-(3-bromophenethyl)cyclohexanol with2-(prop-2-ynyl)isoindoline-1,3-dione following the method described inExample 12 gives2-(3-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)prop-2-ynyl)isoindoline-1,3-dione.

Step 2: Deprotection of2-(3-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)prop-2-ynyl)isoindoline-1,3-dionefollowing the method described in Example 12 gives Example 184.

Example 185 Preparation of 4-(3-(3-aminopropoxy)phenethyl)heptan-4-OL

4-(3-(3-Aminopropoxy)phenethyl)heptan-4-ol is prepared following themethod used Example 9.

Example 186 Preparation of4-(3-((2-aminoethoxy)methyl)phenethyl)heptan-4-ol

4-(3-((2-Aminoethoxy)methyl)phenethyl)heptan-4-ol is prepared followingthe method shown in Scheme 41.

Step 1: A solution of DIBAL-H in heptane is added under an inertatmosphere to a cooled (−78° C.) solution of2-(3-bromophenyl)-1,3-dioxolane in hexanes. The reaction mixture isstirred until no starting material is seen by TLC. Aqueous HCl (1N) isadded to the reaction mixture while warming to room temperature. Theproduct is extracted with EtOAc. Combined organic layers are dried overanhydrous MgSO₄, and concentrated under reduced pressure to give2-(3-bromobenzyloxy)ethanol.

Step 2: Mitsunobu reaction of 2-(3-bromobenzyloxy)ethanol andphthalimide following the method used in Example 134 gives2-(2-(3-bromobenzyloxy)ethyl)isoindoline-1,3-dione.

Step 3: Sonogashira coupling of2-(2-(3-bromobenzyloxy)ethyl)isoindoline-1,3-dione and4-ethynylheptan-4-ol following the method described in Example 12 gives2-(2-(3-(3-hydroxy-3-propylhex-1-ynyl)benzyloxy)ethyl)isoindoline-1,3-dione.

Step 4:Hydrogenation of2-(2-(3-(3-hydroxy-3-propylhex-1-ynyl)benzyloxy)ethyl)isoindoline-1,3-dionefollowing the method used in Example 12 gives2-(2-(3-(3-hydroxy-3-propylhexyl)benzyloxy)ethyl)isoindoline-1,3-dione.Step 5: Deprotection of2-(2-(3-(3-hydroxy-3-propylhexyl)benzyloxy)ethyl)isoindoline-1,3-dionefollowing the method used in Example 21 gives Example 186.

Example 187 Preparation of 2-(3-(3-aminopropyl)phenethyl)cyclohexanol

2-(3-(3-aminopropyl)phenethyl)cyclohexanol was prepared following themethod used in Example 2:

Step 1: Sonogashira coupling of bromide (10) with 2-ethynylcyclohexanol,followed by flash chromatography (5-50% EtOAc/hexanes gradient), gave2,2,2-trifluoro-N-(3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamideas a yellow oil. Yield (1.2 g, 43%): ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.28(m, 3H), 7.06-7.11 (m, 1H), 6.33 (brs, 1H), 3.48-3.57 (m, 1H), 3.36(ddd, J=6.8 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.38-2.46 (m, 1H), 2.32(brs, 1H), 2.02-2.10 (m, 2H), 1.91 (dddd, J=7.2 Hz, 2H), 1.74-1.82 (m,1H), 1.66-1.74 (m, 1H), 1.40-1.52 (m, 1H), 1.16-1.40 (m, 3H).

Step 2: Deprotection of2,2,2-trifluoro-N-(3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamidefollowed by flash chromatography (10% (7N NH₃/MeOH)/dichloromethane)gave 2-((3-(3-aminopropyl)phenyl)ethynyl)cyclohexanol as an orange oil.Yield (0.606 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.26 (m, 3H),7.08-7.12 (m, 1H), 3.48-3.56 (m, 1H), 2.71 (t, J=7.2 Hz, 2H), 2.61 (t,J=7.2 Hz, 2H), 2.38-2.46 (m, 1H), 2.01-2.10 (m, 2H), 1.64-1.82 (m, 7H),1.40-1.52 (m, 1H), 1.16-1.40 (m, 3H).

Step 3: Hydrogenation of2-((3-(3-aminopropyl)phenyl)ethynyl)cyclohexanol followed by flashchromatography (10% (7N NH₃/MeOH)/dichloromethane) gave example 187 as apale yellow solid. (0.265 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ 7.17 (tJ=7.6 Hz, 1H), 6.96-7.04 (m, 3H), 3.18 (m, 1H), 2.66-2.76 (m, 3H), 2.62(t, J=7.8 Hz, 2H), 2.46-2.56 (m, 1H), 2.05-2.15 (m, 1H), 1.88-1.98 (m,2H), 1.69-1.80 (m, 3H), 1.61-1.69 (m, 1H), 1.34-1.46 (m, 4H), 1.10-1.34(m, 4H), 0.91-1.03 (m, 1H).

Example 188 In Vitro Isomerase Inhibition Assay

The capability of amine derivative compounds to inhibit the activity ofa visual cycle isomerase was determined.

Isomerase inhibition reactions were performed essentially as described(Stecher et al., J. Biol. Chem. 274:8577-85 (1999); see also Golczak etal., Proc. Natl. Acad. Sci. USA 102:8162-67 (2005)). Bovine RetinalPigment Epithelium (RPE) microsome membranes were the source of a visualcycle isomerase.

RPE Microsome Membrane Preparation

Bovine RPE microsome membrane extracts were prepared according tomethods described (Golczak et al., Proc. Natl. Acad. Sci. USA102:8162-67 (2005)) and stored at −80° C. Crude RPE microsome extractswere thawed in a 37° C. water bath, and then immediately placed on ice.50 ml crude RPE microsomes were placed into a 50 ml Teflon-glasshomogenizer (Fisher Scientific, catalog no. 0841416M) on ice, powered bya hand-held DeWalt drill, and homogenized ten times up and down on iceunder maximum speed. This process was repeated until the crude RPEmicrosome solution was homogenized. The homogenate was then subjected tocentrifugation (50.2 Ti rotor (Beckman, Fullerton, Calif.), 13,000 RPM;15360 Rcf) for 15 minutes at 4° C. The supernatant was collected andsubjected to centrifugation at 42,000 RPM (160,000 Rcf; 50.2 Ti rotor)for 1 hour at 4° C. The supernatant was removed, and the pellets weresuspended in 12 ml (final volume) cold 10 mM MOPS buffer, pH 7.0. Theresuspended RPE membranes in 5 ml aliquots were homogenized in aglass-to-glass homogenizer (Fisher Scientific, catalog no. K885500-0021)to high homogeneity. Protein concentration was quantified using the BCAprotein assay according to the manufacturer's protocol (Pierce,Rockford, Ill.). The homogenized RPE preparations were stored at −80° C.

Isolation of Human Apo Cellular Retinaldehyde-Binding Protein (CRALBP)

Recombinant human apo cellular retinaldehyde-binding protein (CRALBP)was cloned and expressed according to standard methods in the molecularbiology art (see Crabb et al., Protein Science 7:746-57 (1998); Crabb etal., J. Biol. Chem. 263:18688-92 (1988)). Briefly, total RNA wasprepared from confluent ARPE19 cells (American Type Culture Collection,Manassas, Va.), cDNA was synthesized using an oligo(dT)₁₂₋₁₈ primer, andthen DNA encoding CRALBP was amplified by two sequential polymerasechain reactions (see Crabb et al., J. Biol. Chem. 263:18688-92 (1988);Intres, et al., J. Biol. Chem. 269:25411-18 (1994); GenBank AccessionNo. L34219.1). The PCR product was sub-cloned into pTrcHis2-TOPO TAvector according to the manufacturer's protocol (Invitrogen Inc.,Carlsbad, Calif.; catalog no. K4400-01), and then the sequence wasconfirmed according to standard nucleotide sequencing techniques.Recombinant 6×His-tagged human CRALBP was expressed in One Shot TOP 10chemically competent E. coli cells (Invitrogen), and the recombinantpolypeptide was isolated from E. coli cell lysates by nickel affinitychromatography using nickel (Ni) Sepharose XK16-20 columns for HPLC(Amersham Bioscience, Pittsburgh, Pa.; catalog no. 17-5268-02). Thepurified 6×His-tagged human CRALBP was dialyzed against 10 mMbis-tris-Propane (BTP) and analyzed by SDS-PAGE. The molecular weight ofthe recombinant human CRALBP was approximately 39 kDal.

Isomerase Assay

Amine derivative compounds and control compounds were reconstituted inethanol to 0.1 M. Ten-fold serial dilutions (10⁻², 10⁻³, 10⁻⁴, 10⁻⁵,10⁻⁶ M) in ethanol of each compound were prepared for analysis in theisomerase assay.

The isomerase assay was performed in 10 mM bis-tris-propane (BTP)buffer, pH 7.5, 0.5% BSA (diluted in BTP buffer), 1 mM sodiumpyrophosphate, 20 μM all-trans retinol (in ethanol), and 6 μMapo-CRALBP. The test compounds (2 μl) (final 1/15 dilution of serialdilution stocks) were added to the above reaction mixture to which RPEmicrosomes were added. The same volume of ethanol was added to thecontrol reaction (absence of test compound). Bovine RPE microsomes (9μl) (see above) were then added, and the mixtures transferred to 37° C.to initiate the reaction (total volume=150 μl). The reactions werestopped after 30 minutes by adding methanol (300 μl). Heptane was added(300 μl) and mixed into the reaction mixture by pipetting. Retinoid wasextracted by agitating the reaction mixtures, followed by centrifugationin a microcentrifuge. The upper organic phase was transferred to HPLCvials and then analyzed by HPLC using an Agilent 1100 HPLC system withnormal phase column: SILICA (Agilent Technologies, dp 5μ, 4.6 mmX, 25CM;running method had flow rate of 1.5 ml/min; injection volume 100 μl).The solvent components were 20% of 2% isopropanol in EtOAc and 80% of100% hexane.

The area under the A₃₁₈ nm curve represents the 11-cis retinol peak,which is calculated by Agilent Chemstation software and recordedmanually. The IC₅₀ values (concentration of compound that gives 50%inhibition of 11-cis retinol formation in vitro) are calculated usingGraphPad Prism® 4 Software (Irvine, Calif.). All tests are performed induplicate.

The concentration dependent effect of the compounds disclosed herein onthe retinol isomerization reaction can also be evaluated with arecombinant human enzyme system. In particular, the in vitro isomeraseassay was performed essentially as in Golczak et al. 2005, PNAS 102:8162-8167, ref. 3). A homogenate of HEK293 cell clone expressingrecombinant human RPE65 and LRAT were the source of the visual enzymes,and exogenous all-trans-retinol (about 20 μM) was used as the substrate.Recombinant human CRALBP (about 80 μg/mL) was added to enhance theformation of 11 cis-retinal. The 200 μL Bis-Tris Phosphate buffer (10mM, pH 7.2) based reaction mixture also contains 0.5% BSA, and 1 mMNaPPi. In this assay, the reaction was carried out at 37° C. induplicates for one hour and was terminated by addition of 300 μLmethanol. The amount of reaction product, 11-cis-retinol, was measuredby HPLC analysis following Heptane extraction of the reaction mixture.The Peak Area Units (PAUs) corresponding to 11 cis-retinol in the HPLCchromatograms were recorded and concentration dependent curves analyzedby GraphPad Prism for IC₅₀ values. The ability of the numerous compoundsdisclosed herein to inhibit isomerization reaction is quantified and therespective IC₅₀ value is determined. The tables below summarises theIC₅₀ values of various compounds of the present invention determined byeither of the above two methods. IC₅₀s for human and bovine in vitrodata are provided in Tables 6A and 6B.

TABLE 6 Human In Vitro Inhibition Data IC₅₀ (μM) Compound/Example Number≦0.01 μM   9, 19, 20, 59, 71, 73, 90, 102, 100, 110 >0.01 μM-≦0.1 μM  3,7, 10, 11, 12, 14, 15, 16, 17, 18, 24, 25, 30, 33, 41, 42, 45, 46, 47,48, 49, 50, 54, 58, 60, 61, 63, 64, 68, 70, 72, 77, 79, 80, 82, 84, 85,89, 91, 92, 95, 97, 98, 99, 104, 105, 106, 109, 113, 114, 115, 116, 124,133, 134, 137, 138, 140, 144, 145, 147, 150, 154, 155, 156, 157, 158,162, 164, 187 >0.1 μM-≦1 μM   22, 26, 27, 28, 31, 35, 36, 38, 39, 40,51, 52, 53, 55, 57, 62, 65, 66, 67, 69, 74, 75, 76, 78, 79, 81, 86, 87,88, 101, 103, 107, 108, 111, 112, 117, 118, 121, 122, 123, 127, 128,130, 131, 132, 135, 136, 139, 142, 143, 146, 149, 151, 152, 153, 159,160, 161, 165  >1 μM-≦10 μM 37, 43, 56, 83, 93, 94, 96, 120, 125, 126,129, 148, 163 >10 μM 44, 141 No detectable activity 119 Bovine In VitroInhibition data IC₅₀ (μM) Compound/Example Number ≦1 μM 2, 3, 7, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 26, 27, 28, 29, 30, 33,35, 38 >1 μM-≦10 μM 1, 4, 5, 8, 22, 31, 34, 36, 37 >10 μM-≦100 μM 6, 21,23, 32 >100 μM-≦1000 μM 166

Example 189 In Vivo Murine Isomerase Assay

The capability of amine derivative compounds to inhibit isomerase wasdetermined by an in vivo murine isomerase assay. Brief exposure of theeye to intense light (“photobleaching” of the visual pigment or simply“bleaching”) is known to photo-isomerize almost all 11-cis-retinal inthe retina. The recovery of 11-cis-retinal after bleaching can be usedto estimate the activity of isomerase in vivo. Delayed recovery, asrepresented by lower 11-cis-retinal oxime levels, indicates inhibitionof isomerization reaction. Procedures were performed essentially asdescribed by Golczak et al., Proc. Natl. Acad. Sci. USA 102:8162-67(2005). See also Deigner et al., Science, 244: 968-71 (1989); Gollapalliet al., Biochim Biophys Acta. 1651: 93-101 (2003); Parish, et al., Proc.Natl. Acad. Sci. USA, 14609-13 (1998); Radu, et al., Proc Natl Acad SciUSA 101: 5928-33 (2004).

Six-week old dark-adapted CD-1 (albino) male mice were orally gavagedwith compound (0.03-3 mg/kg) dissolved in 100 μl corn oil containing 10%ethanol (5-8 animals per group). Mice were orally gavaged with theseveral of the amine derivative compounds described herein. After 1-48hours in the dark, the mice were exposed to photobleaching of 5,000 luxof white light for 10 minutes. The mice were allowed to recover 2 hoursin the dark. The animals were then sacrificed by carbon dioxideinhalation. Retinoids were extracted from the eye and the regenerationof 11-cis-retinal was assessed at various time intervals.

Eve Retinoid Extraction

All steps were performed in darkness with minimal redlight illumination(low light darkroom lights and redfiltered flashlights for spotillumination as needed) (see, e.g., Maeda et al., J. Neurochem85:944-956, 2003; Van Hooser et al., J Biol Chem 277:19173-82, 2002).After the mice were sacrificed, the eyes were immediately removed andplaced in liquid nitrogen for storage.

The eyes were placed in 500 L of bis-tris propane buffer (10 mM, pH˜7.3) and 20 L of 0.8M hydroxylamine (pH˜7.3). The eyes were cut up intosmall pieces with small iris scissors and then thoroughly homogenized at30000 rpm with a mechanical homogenizer (Polytron PT 1300 D) in the tubeuntil no visible tissue remained. 500 L of methanol and 500 L of heptanewere added to each tube. The tubes were attached to a vortexer so thatthe contents were mixed thoroughly for 15 minutes in room temperature.The organic phase was separated from the aqueous phase by centrifugationfor 10 min at 13K rpm, 4° C. 240 L of the solution from the top layer(organic phase) was removed and transferred to clean 300 μl glassinserts in HPLC vials using glass pipette and the vials were crimpedshut tightly.

The samples were analyzed on an Agilent 1100 HPLC system with normalphase column: SILICA (Beckman Coutlier, dp 5 μm, 4.6 mM×250 mM). Therunning method has a flow rate of 1.5 ml/min; solvent components are 15%solvent 1 (1% isopropanol in ethyl acetate), and 85% solvent 2 (100%hexanes). Loading volume for each sample is 100 μl; detection wavelengthis 360 nm. The area under the curve for 11-cis retinal oxime wascalculated by Agilent Chemstation software and was recorded manually.Data processing was performed using Prizm software.

Positive control mice (no compound administered) were sacrificed fullydark-adapted and the eye retinoids analyzed. Light (bleached) controlmice (no compound administered) were sacrificed and retinoids isolatedand analyzed immediately after light treatment. As an example, theisomerase inhibitory activity of the compound of Example 3 (Compound 3)is presented in FIG. 1. The animals were orally gavaged with 1 mg/kgcompound, then “photo-bleached” (5000 Lux white light for 10 minutes) at4, 24 and 48 hours after dosing, and returned to darkness to allowrecovery of the 11-cis-retinal content of the eyes. Mice were sacrificed2 hours after bleaching, eyes were enucleated, and retinoid content wasanalyzed by HPLC. Results are presented in FIG. 1.

A dose response in vivo isomerase inhibition study was performed withseveral of the amine derivative compounds described herein. Six-week olddark-adapted CD-1 (albino) male mice were orally gavaged with 0.03, 0.1,0.3, 1 and 3 mg/kg of compound in sterile water as solution, andphotobleached 4 hours after dosing. The mice were allowed to recover 2hours in the dark. The animals were then sacrificed by carbon dioxideinhalation. Retinoids were extracted from the eye and the regenerationof 11-cis-retinal was assessed at various time intervals. Retinoidanalysis was performed as described above. Dark control mice werevehicle-only treated, sacrificed fully dark adapted without lighttreatment, and analyzed. As an example, the dose-dependent inhibition ofthe recovery of 11-cis retinal (oxime) at 4 hours post dosing of thecompound of Example 19 (Compound 19) is presented in FIG. 2. FIG. 2Ashows dose-dependent inhibition of isomerase activity and FIG. 2B showsthe dose response (log dose, mg/kg) in which the data are normalized topercent inhibition of isomerase activity. Four animals were included ineach treatment group. The error bars correspond to standard error.Inhibition of recovery was dose related, with the ED₅₀ (dose of compoundthat gives 50% inhibition of 11-cis retinal (oxime) recovery) estimatedat 0.651 mg/kg. The estimated ED₅₀ of compounds of Examples 3, 29, 15and 19 (Compounds 3, 29, 15 and 19) are presented in Table 7A.

TABLE 7A IN VIVO INHIBITION DATA Compound ED₅₀ (mg/kg) 3 2 29 4 15 2 190.65

A single dose study of several of the compounds disclosed herein wasperformed, at 1 mg/kg and in some cases also 5 mg/kg oral dosing, withphotobleaching 4 and 24 hours post dosing. The experiments were alsocarried out in CD1 male mice. Results were analyzed by HPLC. %Inhibition results are presented in Table 7B.

TABLE 7B IN VIVO INHIBITION DATA % Inhibition % Inhibition 1 mg/kg 5mg/kg Example No. 4 h 24 h 4 h 24 h 3 36 13 95 0 7 23 12 9 12 6 10 9 111 0 0 12 27 12 16 6 0 17 84 0 20 0 2 27 6 29 29 0 0 62 0 35 0 59 14 7167 70 100 85 70 90 84 99 22 100 9 109 79 110 61 113 87 134 6 140 87 1570 164 0 187 9

Example 190 Preparation of Retinal Neuronal Cell Culture System

This example describes methods for preparing a long-term culture ofretinal neuronal cells. All compounds and reagents can be obtained fromSigma Aldrich Chemical Corporation (St. Louis, Mo.) or other suitablevendors.

Retinal Neuronal Cell Culture

Porcine eyes are obtained from Kapowsin Meats, Inc. (Graham, Wash.).Eyes are enucleated, and muscle and tissue are cleaned away from theorbit. Eyes are cut in half along their equator and the neural retina isdissected from the anterior part of the eye in buffered saline solution,according to standard methods known in the art. Briefly, the retina,ciliary body, and vitreous are dissected away from the anterior half ofthe eye in one piece, and the retina is gently detached from the clearvitreous. Each retina is dissociated with papain (WorthingtonBiochemical Corporation, Lakewood, N.J.), followed by inactivation withfetal bovine serum (FBS) and addition of 134 Kunitz units/ml of DNaseI.The enzymatically dissociated cells are triturated and collected bycentrifugation, resuspended in Dulbecco's modified Eagle's medium(DMEM)/F12 medium (Gibco BRL, Invitrogen Life Technologies, Carlsbad,Calif.) containing about 25 μg/ml of insulin, about 100 μg/ml oftransferrin, about 60 μM putrescine, about 30 nM selenium, about 20 nMprogesterone, about 100 U/ml of penicillin, about 100 μg/ml ofstreptomycin, about 0.05 M Hepes, and about 10% FBS. Dissociated primaryretinal cells are plated onto Poly-D-lysine- and Matrigel-(BD, FranklinLakes, N.J.) coated glass coverslips that are placed in 24-well tissueculture plates (Falcon Tissue Culture Plates, Fisher Scientific,Pittsburgh, Pa.). Cells are maintained in culture for 5 days to onemonth in 0.5 ml of media (as above, except with only 1% FBS) at 37° C.and 5% CO₂.

Immunocvtochemistry Analysis

The retinal neuronal cells are cultured for about 1, 3, 6, and 8 weeks,and the cells are analyzed by immunohistochemistry at each time point.Immunocytochemistry analysis is performed according to standardtechniques known in the art. Rod photoreceptors are identified bylabeling with a rhodopsin-specific antibody (mouse monoclonal, dilutedabout 1:500; Chemicon, Temecula, Calif.). An antibody to mid-weightneurofilament (NFM rabbit polyclonal, diluted about 1:10,000, Chemicon)is used to identify ganglion cells; an antibody to 33-tubulin (G7121mouse monoclonal, diluted about 1:1000, Promega, Madison, Wis.) is usedto generally identify interneurons and ganglion cells, and antibodies tocalbindin (AB1778 rabbit polyclonal, diluted about 1:250, Chemicon) andcalretinin (AB5054 rabbit polyclonal, diluted about 1:5000, Chemicon)are used to identify subpopulations of calbindin- andcalretinin-expressing interneurons in the inner nuclear layer. Briefly,the retinal cell cultures are fixed with 4% paraformaldehyde(Polysciences, Inc, Warrington, Pa.) and/or ethanol, rinsed inDulbecco's phosphate buffered saline (DPBS), and incubated with primaryantibody for about 1 hour at 37° C. The cells are then rinsed with DPBS,incubated with a secondary antibody (Alexa 488- or Alexa 568-conjugatedsecondary antibodies (Molecular Probes, Eugene, Oreg.)), and rinsed withDPBS. Nuclei are stained with 4′, 6-diamidino-2-phenylindole (DAPI,Molecular Probes), and the cultures are rinsed with DPBS before removingthe glass coverslips and mounting them with Fluoromount-G (SouthernBiotech, Birmingham, Ala.) on glass slides for viewing and analysis.

Survival of mature retinal neurons after varying times in culture isindicated by the histochemical analyses. Photoreceptor cells areidentified using a rhodopsin antibody; ganglion cells are identifiedusing an NFM antibody; and amacrine and horizontal cells are identifiedby staining with an antibody specific for calretinin.

Cultures are analyzed by counting rhodopsin-labeled photoreceptors andNFM-labeled ganglion cells using an Olympus IX81 or CZX41 microscope(Olympus, Tokyo, Japan). About twenty fields of view are counted percoverslip with a 20× objective lens. At least five coverslips areanalyzed by this method for each condition in each experiment. Cellsthat are not exposed to any stressor are counted, and cells exposed to astressor are normalized to the number of cells in the control. It isexpected that compounds presented in this disclosure promotedose-dependent and time-dependent survival of mature retinal neurons.

Example 191 Effect of Amine Derivative Compounds on Retinal CellSurvival

This Example describes the use of the mature retinal cell culture systemthat comprises a cell stressor for determining the effects of an aminederivative compound on the viability of the retinal cells.

Retinal cell cultures are prepared as described in Example 190. A2E isadded as a retinal cell stressor. After culturing the cells for about 1week, a chemical stress, A2E, is applied. A2E is diluted in ethanol andadded to the retinal cell cultures at concentration of about 0, 10 μM,20 μM, and 40 μM. Cultures are treated for about 24 and 48 hours. A2E isobtained from Dr. Koji Nakanishi (Columbia University, New York City,N.Y.) or is synthesized according to the method of Parish et al. (Proc.Natl. Acad. Sci. USA 95:14602-13 (1998)). An amine derivative compoundis then added to the culture. To other retinal cell cultures, an aminederivative compound is added before application of the stressor or isadded at the same time that A2E is added to the retinal cell culture.The cultures are maintained in tissue culture incubators for theduration of the stress at 37° C. and 5% CO₂. The cells are then analyzedby immunocytochemistry as described in Example 190.

Apoptosis Analysis

Retinal cell cultures are prepared as described in Example 190 andcultured for about 2 weeks and then exposed to white light stress atabout 6000 lux for about 24 hours followed by about a 13-hour restperiod. A device was built to uniformly deliver light of specifiedwavelengths to specified wells of the 24-well plates. The devicecontains a fluorescent cool white bulb (GE P/N FC12T9/CW) wired to an ACpower supply. The bulb is mounted inside a standard tissue cultureincubator. White light stress is applied by placing plates of cellsdirectly underneath the fluorescent bulb. The CO₂ levels are maintainedat about 5%, and the temperature at the cell plate is maintained at 37°C. The temperature is monitored by using thin thermocouples. The lightintensities for all devices are measured and adjusted using a lightmeter from Extech Instruments Corporation (P/N 401025; Waltham, Mass.).Any amine derivative compound is added to wells of the culture platesprior to exposure of the cells to white light and is added to otherwells of the cultures after exposure to white light. To assessapoptosis, TUNEL is performed as described herein.

Apoptosis analysis is also performed after exposing retinal cells toblue light. Retinal cell cultures are cultured as described in Example190. After culturing the cells for about 1 week, a blue light stress isapplied. Blue light is delivered by a custom-built light-source, whichconsists of two arrays of 24 (4×6) blue light-emitting diodes (SunbriteLED P/N SSP-01TWB7UWB12), designed such that each LED is registered to asingle well of a 24 well disposable plate. The first array is placed ontop of a 24 well plate full of cells, while the second one is placedunderneath the plate of cells, allowing both arrays to provide a lightstress to the plate of cells simultaneously. The entire apparatus isplaced inside a standard tissue culture incubator. The CO₂ levels aremaintained at about 5%, and the temperature at the cell plate ismaintained at about 37° C. The temperature is monitored with thinthermocouples. Current to each LED is controlled individually by aseparate potentiometer, allowing a uniform light output for all LEDs.Cell plates are exposed to about 2000 lux of blue light stress foreither about 2 hours or 48 hours, followed by a about 14-hour restperiod. An amine derivative compound is added to wells of the cultureplates prior to exposure of the cells to blue light and is added toother wells of the cultures after exposure to blue light. To assessapoptosis, TUNEL is performed as described herein.

To assess apoptosis, TUNEL is performed according to standard techniquespracticed in the art and according to the manufacturer's instructions.Briefly, the retinal cell cultures are first fixed with 4%paraformaldehyde and then ethanol, and then rinsed in DPBS. The fixedcells are incubated with TdT enzyme (0.2 units/μl final concentration)in reaction buffer (Fermentas, Hanover, Md.) combined with Chroma-TideAlexa568-5-dUTP (0.1 μM final concentration) (Molecular Probes) forabout 1 hour at 37° C. Cultures are rinsed with DPBS and incubated withprimary antibody either overnight at 4° C. or for about 1 hour at 37° C.The cells are then rinsed with DPBS, incubated with Alexa 488-conjugatedsecondary antibodies, and rinsed with DPBS. Nuclei are stained withDAPI, and the cultures are rinsed with DPBS before removing the glasscoverslips and mounting them with Fluoromount-G on glass slides forviewing and analysis.

Cultures are analyzed by counting TUNEL-labeled nuclei using an OlympusIX81 or CZX41 microscope (Olympus, Tokyo, Japan). Twenty fields of vieware counted per coverslip with a 20× objective lens. Six coverslips areanalyzed by this method for each condition. Cells that are not exposedto an amine derivative compound are counted, and cells exposed to theantibody are normalized to the number of cells in the control. Data areanalyzed using the unpaired Student's t-test. It is expected that aminederivative compounds reduce A2E-induced apoptosis and cell death inretinal cell cultures in a dose-dependent and time-dependent manner.

Example 192 In Vivo Light Mouse Model

This Example describes the effect of an amine derivative compound in anin vivo light damage mouse model.

Exposure of the eye to intense white light can cause photo-damage to theretina. The extent of damage after light treatment can be evaluated bymeasuring cytoplasmic histone-associated-DNA-fragment (mono- andoligonucleosomes) content in the eye (see, e.g., Wenzel et al., Prog.Retin. Eye Res. 24:275-306 (2005)).

Dark adapted mice (for example, male Balb/c (albino, 10/group)) aregavaged with the amine derivative compounds of the present disclosure atvarious doses (about 0.01-25 mg/kg) or vehicle only is administered.

About six hours after dosing, the animals are subjected to lighttreatment (about 8,000 lux of white light for about 1 hour). Mice aresacrificed after about 40 hours of recovery in dark, and retinas aredissected. A cell death detection ELISA assay is performed according tothe manufacturer's instructions (such as ROCHE APPLIED SCIENCE, CellDeath Detection ELISA plus Kit). Contents of fragmented DNA in theretinas are measured to estimate the retinal-protective activity of thecompounds. It is expected that compounds of the present disclosuremitigate or inhibit photo-damage to the retina.

Example 193 Electroretinographic (Erg) Study

This example describes determining the effect of an amine derivativecompound that is a visual cycle modulator on the magnitude of the ERGresponse in the eyes of mice after oral dosing of the animals with thecompound. The level of ERG response in the eyes is determined afteradministering the compound to the animals (for example at about 18 and66 hours post administration).

Three groups of about nine-week old mice (about 19-25 grams), bothgenders (strain C5 7BL/6, Charles River Laboratories, Wilmington, Mass.)are housed at room temperature, 72±4° F., and relative humidity ofapproximately 25%. Animals are housed in a 12-hour light/dark cycleenvironment, have free access to feed and drinking water and are checkedfor general health and well-being prior to use and during the study.Body weights are determined for a representative sample of mice prior toinitiation of dosing. The average weight determined from this samplingis used to establish the dose for all mice in the study.

Each test compound is dissolved in the control solvent (EtOH), anddiluted about 1:10 (90 ml/900 ml) in the appropriate oil (for examplecorn oil (Crisco Pure Corn Oil, J. M. Smucker Company, Orrville, Ohio))to the desired dose (mg/kg) in the desired volume (about 0.1 mL/animal).The control vehicle is ethanol: oil (about 1:10 (0.9 ml/9 ml)). Anexample of treatment designations and animal assignments are describedin Table 8.

TABLE 8 Dose Group Route Treatment (mg/kg) Animals Test oral Aminederivative (~0.01-25 mg/kg) >4 compound Control oral Vehicle None >4

Animals are dosed once orally by gavage, with the assigned vehiclecontrol or test compounds during the light cycle (between about 30 minand about 3 hours 30 min after the beginning of the light cycle). Thevolume of the administered dose usually does not exceed about 10 mL/kg.

ERG recordings are made on dark-adapted and, subsequently (during thecourse of the same experiment), on light-adapted states. For thedark-adapted response, animals are housed in a dark-adapted environmentfor at least about 1 hour prior to the recording, commencing at leastabout 30 minutes after the start of the light cycle.

At about eighteen and about sixty six hours after dosing, the mice areanesthetized with a mixture of Ketamine and Xylazine (100 mg/kg and 20mg/kg, respectively) and placed on a heating pad to maintain stable corebody temperature during the course of the experiment. Pupils are dilatedby placing about a 5 microliter drop of mydriatic solution (tropicamide0.5%) in the recorded eye. A mouse corneal monopolar contact lenselectrode (Mayo Corporation, Inazawa, Aichi, Japan) is placed on thecornea, and a subcutaneous reference low profile needle 12 mm electrode(Grass Telefactor, W Warwick, R.I.) is placed medial from the eye. Aground needle electrode is placed in the tail. Data collection isobtained using an Espion E² (Diagnosys LLC, Littleton, Mass.) ERGrecording system with Color Dome Ganzfeld stimulator. Full dark-adaptedintensity-response function is determined following a brief white flashstimuli of about 14 intensities ranging from about 0.0001 cd·s/m² toabout 333 cd·s/m². Subsequently, full light-adapted intensity-responsefunction is determined following a brief white flash stimuli of about 9intensities ranging from about 0.33 cd·s/m² to about 333 cd·s/m².Analysis of the obtained responses is done off-line. Intensity-responsefunction determination is done by fitting a sigmoid function to the data(Naka K I, Rushton Wash., 1966; Naka K I, Rushton Wash., 1967). It isexpected that amine derivative compounds of the present disclosure willdepress or suppress the dark-adapted ERG responses (measured at about0.01 cd·s/m²) while minimally affecting the photopic, light-adaptedV_(max) values when compared to control compounds.

Example 194 Effect of an Amine Derivative Compound on Reduction ofLipofuscin Fluorophores

This example describes testing the capability of an amine derivativecompound to reduce the level of existing bis-retinoid,N-retinylidene-N-retinylethanolamine (A2E) and lipofuscin fluorophoresin the retina of mice as well as prevention of the formation of A2E andlipofuscin fluorophores. A2E is the major fluorophore of toxiclipofuscin in ocular tissues.

The eyes of abca4-null (abca4−/−) mutant mice (see, e.g., Weng et al.,Cell 98:13-23 (1999) have an increased accumulation of lipofuscinfluorophores, such as A2E (see, e.g., Karan et al., Proc. Natl. Acad.Sci. USA 102:4164-69 (2005)). Compounds (about 1 mg/kg) or vehicle areadministered daily for about three months by oral gavage to abca4^(−/−)mice that are about 2 months old. Mice are sacrificed after about threemonths of treatment. Retinas and RPE are extracted for A2E analysis.

A similar experiment is performed with aged balb/c mice (about 10 monthsold). The test mice are treated with about 1 mg/kg/day of compounds forabout three months and the control mice are treated with vehicle.

Briefly, under dim red light, each pair of eye balls are harvested,homogenized in a mixture of PBS buffer and methanol and the A2Eextracted into chloroform. The samples are dried down and reconstitutedin a water/acetonitrile mix for HPLC analysis. The amount of A2E presentis determined by comparison of the area under the curve (AUC) of the A2Epeak in the sample with an A2E concentration/AUC curve for an A2Ereference standard measuring at 440 nm.

It is expected that A2E levels are reduced upon treatment with one ormore amine derivative compounds disclosed herein.

Example 195 Effect of an Amine Derivative Compound on Retinoid NuclearReceptor Activity

Retinoid nuclear receptor activity is associated with transduction ofthe non-visual physiologic, pharmacologic, and toxicologic retinoidsignals that affect tissue and organ growth, development,differentiation, and homeostasis.

The effect of one or more amine derivative compounds disclosed hereinand the effect of a retinoic acid receptor (RAR) agonist(E-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl]benzoicacid) (TTNPB), and of all-trans-retinoic acid (at-RA), which is an RARand retinoid X receptor (RXR) agonist, were studied on RAR and RXRreceptors essentially as described by Achkar et al. (Proc. Natl. Acad.Sci. USA 93:4879-84 (1996)). As expected several compounds of thepresent disclosure (Compounds of examples 7, 12, 20, and 16) tested didnot show significant effects on retinoid nuclear receptors (RAR andRXR). By contrast, TTNPB and at-RA activated the RXR_(α), RAR_(α),RAR_(β) and RAR_(γ) receptors as expected (Table 9). Data representcalculated EC50 values (nM)+95% Confidence Interval CI (in parentheses)from 7-point dose-response curves, as calculated by Graph Pad PrismSoftware. Each data point was determined in triplicate.

TABLE 9 RARα RARβ RARγ RXRα Compound EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀(nM) TTNPB 10 (.8-13) 0.4 (.2-.7) 0.1 (.05-.1) ND at-RA NA NA NA 316 +/−57 9-cis RA NA NA NA 1.4 (.45-4.2) Compound 7 NA NA NA NA Compound 12 NANA NA NA Compound 20 NA NA NA NA Compound 16 NA NA NA NA NA = Not active

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The various embodiments described herein can be combined to providefurther embodiments. All U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications, and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet, areincorporated herein by reference in their entireties.

From the foregoing it will be appreciated that, although specificembodiments have been described herein for purposes of illustration,various modifications may be made. Those skilled in the art willrecognize, or be able to ascertain, using no more than routineexperimentation, many equivalents to the specific embodiments describedherein. Such equivalents are intended to be encompassed by the followingclaims. In general, in the following claims, the terms used should notbe construed to limit the claims to the specific embodiments disclosedin the specification and the claims, but should be construed to includeall possible embodiments along with the full scope of equivalents towhich such claims are entitled. Accordingly, the claims are not limitedby the disclosure.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

We claim:
 1. A method for treating an ophthalmic disease or disorderresulting at least in part from lipofuscin pigment accumulated in asubject, comprising administering to the subject a compound, or apharmaceutically acceptable salt, or N-oxide thereof, chosen from:


2. The method of claim 1, wherein the ophthalmic disease or disorder isage related macular degeneration or Stargardt's macular dystrophy.